Novel pyrazolopyridine derivatives as pharmaceutical agents

ABSTRACT

Novel pyrazolopyridine derivative compounds are disclosed and their use as pharmaceutical agents, in particular their use as TGF-beta signal transduction inhibitors useful in the treatment of cancer and other disease states influenced by TGF beta.

The invention relates to new pyrazolopyridine derivative compounds andtheir use as pharmaceutical agents, in particular their use as TGF-betasignal transduction inhibitors.

BACKGROUND OF THE INVENTION

The transforming growth factor-beta (TGF-Beta)(“TGF-β”) polypeptidesinfluence growth, differentiation, and gene expression in many celltypes. The first polypeptide of this family that was characterized,TGF-β1, has two identical 112 amino acid subunits that are covalentlylinked. TGF-β1 is a highly conserved protein with only a single aminoacid difference distinguishing humans from mice. There are two othermembers of the TGF-β gene family that are expressed in mammals. TGF-β2is 71% homologous to TGF-β1 (de Martin, et al. (1987) EMBO J.6:3673-3677), whereas TGF-β3 is 80% homologous to TGF-β1 (Derynck, etal. (1988) EMBO J. 7:3737-3743). The structural characteristics ofTGF-β1 as determined by nuclear magnetic resonance (Archer, et al.(1993) Biochemistry 32:1164-1171) agree with the crystal structure ofTGF-132 (Daopin, et al. (1992) Science 257:369-374; Schlunegger andGrutter (1992) Nature 358:430-434).

There are at least three different extracellular TGF-13 receptors, TypeI, II and III that are involved in the biological functions of TGF-β1,-β2 and -β3 (For reviews, see Derynck (1994) TIBS 19:548-553 andMassague (1990) Ann. Rev. Cell Biol. 6:597-641).

The Type I and Type II receptors are transmembrane serine/threoninekinases which in the presence of TGF-β form a heteromeric signalingcomplex (Wrana, et al (1992) Cell 71: 1003-1014). The mechanism ofactivation of the heteromeric signaling complex at the cell surface hasbeen elucidated (Wrana, et al. (1994) Nature 370: 341-347). TGF-β firstbinds the type II receptor which is a constitutively activetransmembrane serine/threonine kinase. The type I receptor issubsequently recruited into the complex, phoshorylated at the GS domainand activated to phosphorylate downstream signaling components (e.g.Smad proteins) to initiate the intracellular signaling cascade. Aconstitutively active type I receptor (T204D mutant) has been shown toeffectively transduce TGF-β responses, thus bypassing the requirementfor TGF-β and the type II receptor (Wieser, et al. (1995) EMBO J. 14:2199-2208). Although no signaling function has been discovered for thetype III receptor, it does increase TGF-β2's affinity for the type IIreceptor making it essentially equipotent with TGF-β1 and TGF-β3(Lopez-Casillas, et al. (1993) Cell 73: 1435-1444).

Vascular endothelial cells lack the Type III receptor. Insteadendothelial cells express a structurally related protein called endoglin(Cheifetz, et al. (1992) J. Biol. Chem. 267:19027-19030), which onlybinds TGF-β1 and TGF-β3 with high affinity. Thus, the relative potencyof the TGF-β's reflect the type of receptors expressed in a cell andorgan system. In addition to the regulation of the components in themulti-factorial signaling pathway, the distribution of the synthesis ofTGF-β polypeptides also affects physiological function. The distributionof TGF-β2 and TGF-β3 is more limited (Derynck, et al. (1988) EMBO J.7:3737-3743) than TGF-β1, e.g., TGF-β3 is limited to tissues ofmesenchymal origin, whereas TGF-β1 is present in both tissues ofmesenchymal and epithelial origin.

TGF-β1 is a multifunctional cytokine critical for tissue repair. Highconcentrations of TGF-β1 are delivered to the site of injury by plateletgranules (Assoian and Sporn (1986) J. Cell Biol. 102:1217-1223). TGF-β1initiates a series of events that promote healing including chemotaxisof cells such as leukocytes, monocytes and fibroblasts, and regulationof growth factors and cytokines involved in angiogenesis, cell divisionassociated with tissue repair and inflammatory responses. TGF-β1 alsostimulates the synthesis of extracellular matrix components (Roberts, etal. (1986) Proc. Natl. Acad. Sci. USA 83:4167-4171; Spom, et al. (1983)Science 219:1329-1330; Massague (1987) Cell 49:437-438) and mostimportantly for understanding the pathophysiology of TGF-1, TGF-β1autoregulates its own synthesis (Kim, et al. (1989) J. Biol. Chem.264:7041-7045).

A number of diseases have been associated with TGF-β1 over production.Fibrotic diseases associated with TGF-β1 overproduction can be dividedinto chronic conditions such as fibrosis of the kidney, lung and liverand more acute conditions such as dermal scarring and restenosis.Synthesis and secretion of TGF-β1 by tumor cells can also lead to immunesuppression such as seen in patients with aggressive brain or breasttumors (Arteaga, et al. (1993) J. Clin. Invest. 92:2569-2576). Thecourse of Leishmanial infection in mice is drastically altered by TGF-β1(Barral-Netto, et al. (1992) Science 257:545-547). TGF-β1 exacerbatedthe disease, whereas TGF-β1 antibodies halted the progression of thedisease in genetically susceptible mice. Genetically resistant micebecame susceptible to Leishmanial infection upon administration ofTGF-1.

The profound effects of TGF-β1 on extracellular matrix deposition havebeen reviewed (Rocco and Ziyadeh (1991) in Contemporary Issues inNephrology v.23, Hormones, autocoids and the kidney. ed. Jay Stein,Churchill Livingston, N.Y. pp. 391-410; Roberts, et al. (1988) Rec.Prog. Hormone Res. 44:157-197) and include the stimulation of thesynthesis and the inhibition of degradation of extracellular matrixcomponents. Since the structure and filtration properties of theglomerulus are largely determined by the extracellular matrixcomposition of the mesangium and glomerular membrane, it is notsurprising that TGF-β1 has profound effects on the kidney. TheAccumulation of Mesangial Matrix in Proliferate Glomerulonephritis(Border, et al. (1990) Kidney Int. 37:689-695) and diabetic nephropathy(Mauer, et al. (1984) J. Clin. Invest. 74:1143-1155) are clear anddominant pathological features of the diseases. TGF-β1 levels areelevated in human diabetic glomerulosclerosis (advanced neuropathy)(Yamamoto, et al. (1993) Proc. Natl. Acad. Sci. 90:1814-1818). TGF-β1 isan important mediator in the genesis of renal fibrosis in a number ofanimal models (Phan, et al. (1990) Kidney Int. 37:426; Okuda, et al.(1990) J. Clin. Invest. 86:453). Suppression of experimentally inducedglomerulonephritis in rats has been demonstrated by antiserum againstTGF-β1 (Border, et al. (1990) Nature 346:371) and by an extracellularmatrix protein, decorin, which can bind TGF-β1 (Border, et al. (1992)Nature 360:361-363).

Too much TGF-β1 leads to dermal scar-tissue formation. NeutralizingTGF-β1 antibodies injected into the margins of healing wounds in ratshave been shown to inhibit scarring without interfering with the rate ofwound healing or the tensile strength of the wound (Shah, et al. (1992)Lancet 339:213-214). At the same time there was reduced angiogenesis,reduced number of macrophages and monocytes in the wound, and a reducedamount of disorganized collagen fiber deposition in the scar tissue.

TGF-β1 may be a factor in the progressive thickening of the arterialwall which results from the proliferation of smooth muscle cells anddeposition of extracellular matrix in the artery afterballoonangioplasty. The diameter of the restenosed artery may be reduced 90% bythis thickening, and since most of the reduction in diameter is due toextracellular matrix rather than smooth muscle cell bodies, it may bepossible to open these vessels to 50% simply by reducing extensiveextracellular matrix deposition. In uninjured pig arteries transfectedin vivo with a TGF-β1 gene, TGF-β1 gene expression was associated withboth extracellular matrix synthesis and hyperplasia (Nabel, et al.(1993) Proc. Natl. Acad. Sci. USA 90:10759-10763). The TGF-β1 inducedhyperplasia was not as extensive as that induced with PDGF-BB, but theextracellular matrix was more extensive with TGF-β1 transfectants. Noextracellular matrix deposition was associated with FGF-1 (a secretedform of FGF) induced hyperplasia in this gene transfer pig model (Nabel(1993) Nature 362:844-846).

There are several types of cancer where TGF-β1 produced by the tumor maybe deleterious. MATLyLu rat cancer cells (Steiner and Barrack (1992)Mol. Endocrinol 6:15-25) and MCF-7 human breast cancer cells (Arteaga,et al. (1993) Cell Growth and Differ. 4:193-201) became more tumorigenicand metastatic after transfection with a vector expressing the mouseTGF-β1. In breast cancer, poor prognosis is associated with elevatedTGF-β (Dickson, et al. (1987) Proc. Natl. Acad. Sci. USA 84:837-841;Kasid, et al. (1987) Cancer Res. 47:5733-5738; Daly, et al. (1990) J.Cell Biochem. 43:199-211; Barrett-Lee, et al. (1990) Br. J. Cancer61:612-617; King, et al. (1989) J. Steroid Biochem. 34:133-138; Welch,et al. (1990) Proc. Natl. Acad. Sci. USA 87:7678-7682; Walker, et al.(1992) Eur. J. Cancer 238:641-644) and induction of TGF-β1 by tamoxifentreatment (Butta, et al. (1992) Cancer Res. 52:4261-4264) has beenassociated with failure of tamoxifen treatment for breast cancer(Thompson, et al. (1991) Br. J. Cancer 63:609-614). Anti TGF-β1antibodies inhibit the growth of MDA-231 human breast cancer cells inathymic mice (Arteaga, et al. (1993) J. Clin. Invest. 92:2569-257.6), atreatment which is correlated with an increase in spleen natural killercell activity. CHO cells transfected with latent TGF-β1 also showeddecreased NK activity and increased tumor growth in nude mice (Wallick,et al. (1990) J. Exp. Med. 172:1777-1784). Thus, TGF-β secreted bybreast tumors may cause an endocrine immune suppression. High plasmaconcentrations of TGF-β1 have been shown to indicate poor prognosis foradvanced breast cancer patients (Anscher, et al. (1993) N. Engl. J. Med.328:1592-1598). Patients with high circulating TGF-β before high dosechemotherapy and autologous bone marrow transplantation are at high riskfor hepatic veno-occlusive disease (15-50% of all patients with amortality rate up to 50%) and idiopathic interstitial pneumonitis(40-60% of all patients). The implication of these findings is 1) thatelevated plasma levels of TGF-β1 can be used to identify at riskpatients and 2) that reduction of TGF-1 could decrease the morbidity andmortality of these common treatments for breast cancer patients.

Many malignant cells secrete transforming growth factor-5 (TGF-β), apotent immunosuppressant, suggesting that TGF-β production may representa significant tumor escape mechanism from host immunosurveillance.Establishment of a leukocyte sub-population with disrupted TGF-βsignaling in the tumor-bearing host offers a potential means forimmunotherapy of cancer. Down regulation of TGF-β secretion in tumorcells results in restoration of immunogenicity in the host, while T-cellinsensitivity to TGF-β results in accelerated differentiation andautoimmunity, elements of which may be required in order to combatself-antigen-expressing tumors in a tolerized host. The rationale,approaches, and potential pitfalls of this strategy will be discussed.Cancer: During the earliest stages of carcinogenesis, TGF-β1 can act asa potent tumor suppressor and may mediate the actions of somechemopreventive agents. However, at some point during the developmentand progression of malignant neoplasms, tumor cells appear to escapefrom TGF-O-dependent growth inhibition in parallel with the appearanceof bioactive TGF-β in the microenvironment. Thus, the production ofTGF-1 by malignant cells in primary tumors appears to increase withadvancing stages of tumor progression. Studies in many of the majorepithelial cancers suggest that the increased production of TGF-β byhuman cancers occurs as a relatively late event during tumorprogression. Further, this tumor-associated TGF-β provides the tumorcells with a selective advantage and promotes tumor progression. Theeffects of TGF-β on cell/cell and cell/stroma interactions result in agreater propensity for invasion and metastasis. Tumor-associated TGF-βmay allow tumor cells to escape from immune surveillance since it is apotent inhibitor of the clonal expansion of activated lymphocytes. TGF-βhas also been shown to inhibit the production of angiostatin. Cancertherapeutic modalities such as radiation therapy and chemotherapy inducethe production of activated TGF-β in the tumor, thereby selectingoutgrowth of malignant cells that are resistant to TGF-β growthinhibitory effects. Thus, these anticancer treatments increase the riskand hasten the development of tumors with enhanced growth andinvasiveness. In this situation, agents targeting TGF-β1 itself might bea very effective therapeutic strategy. The resistance of tumor cells toTGF-β has been shown to negate much of the cytotoxic effects ofradiation therapy and chemotherapy and the treatment-dependentactivation of TGF-D in the stroma may even be detrimental as it can makethe microenvironment more conducive to tumor progression and contributesto tissue damage leading to fibrosis. The development of a TGF-β1neutralizing agent is likely to benefit the treatment of progressedcancer alone and in combination with other therapies.

Epithelial and hematopoietic cells have a high turnover and theirprogenitor cells divide continuously, making them prime targets forgenetic and epigenetic changes that lead to cell transformation andtumorigenesis. The consequent changes in cell behavior andresponsiveness result not only from genetic alterations such asactivation of oncogenes or inactivation of tumor suppressor genes, butalso from altered production of, or responsiveness to, stimulatory orinhibitory growth and differentiation factors.

Among these, transforming growth factor beta (TGF-beta) and itssignaling effectors act as key determinants of carcinoma cell behavior.The autocrine and paracrine effects of TGF-beta on tumor cells and thetumor micro-environment exert both positive and negative influences oncancer development.

Accordingly, the TGF-beta signaling pathway has been considered as botha tumor suppressor pathway and a promoter of tumor progression andinvasion. Derynck, R., Akhurst, R. & Balmain, A., TGF-beta signaling intumor suppression and cancer progression, Nature Genetics, Vol. 29,October, 2001.

SUMMARY OF THE INVENTION

The invention herein disclosed is directed to compounds of thestructure:

Wherein:

-   -   R1 is unsubstituted or substituted pyridine; unsubstituted or        substituted ffiryl; or unsubstituted or substituted thiophenyl;        wherein the substitution may be one or more of the following:        (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylthio,        trifluoromethyl, halo, N-morpholino, phenylthio;    -   R2 is unsubstituted or substituted quinoline; unsubstituted or        substituted phenyl; unsubstituted or substituted naphthalene;        unsubstituted or substituted pyridine; unsubstituted or        substituted pyrimidine; unsubstituted or substituted        quinazoline; unsubstituted or substituted cinnoline;        unsubstituted or substituted indole; unsubstituted or        substituted; unsubstituted or substituted benzofuran;        unsubstituted or substituted dihydrobenzofuran; unsubstituted or        substituted dihydrobenzo[1,4]dioxane; unsubstituted or        substituted benzodioxolane; unsubstituted or substituted        benzothiophene; unsubstituted or substituted        2-aminobenzimidazole; unsubstituted or substituted        imidazo[1,2-a]pyridine; wherein the substitution may        independently be one or more of the following: hydrogen,        (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)        alkylhalide, (C1-C6)alkoxy, (C2-C6)alkenyloxy,        (C2-C6)alkynyloxy, (C1-C6)alkylthio, (C1-C6)alkylsulphinyl,        (C1-C6)alkylsulphonyl, (C1-C6)alkylamino,        di-[(C1-C6)alkyl]amino, (C1-C6)alkoxycarbonyl,        N-(C1-C6)alkylcarbamoyl, N,N-di-[(C1-C6)alkyl]carbamoyl,        aminooxy, N-(C1-C6)alkyl aminooxy,        N,N-di-[(C1-C6)alkyl]aminooxy, (C2-C6)alkanoyl,        (C2-C6)alkanoyloxy, (C2-C6)alkanoylamino,        N-(C1-C6)alkyl-(C2-C6)alkanoylamino, (C3-C6)alkenoylamino,        N-(C1-C6)alkyl-(C3-C6)alkenoylamino, (C3-C6)alkynoylamino,        N-(C1-C6)alkyl-(C3-C6)alkynoylamino, sulphamoyl,        N-(C1-C6)alkylsulphamoyl, N,N-di-[(C1-C6)alkyl]sulphamoyl,        (C1-C6)alkanesulphonylamino,        N-(C1-C6)alkyl-(C1-C6)alkanesulphonyl amino, carboxamide,        ethylene, phenyl, thiophenyl, aminophenyl, phenylthio, halo,        cyano, pyridinyl, arylalkyl, hydroxy, N-pyrrolidino,        N-morpholino, carboxyl, [5-phenyl-1,2,4-oxadiazole-3-yl]methoxy,        6-methyl-pyridazin-3-yl-oxy, (5-oxo-2-pyrrolidinyl)methoxy,        2-(4,5-dihydro-1H-imidazolyl), N,N-dialkylcarbamoyloxy,        1-hydroxy-1-methylethyl, 4-fluorophenyl,        3,4-methylenedioxyphenyl, trifluoromethyl, trifluoromethoxy,        or a group of the formula:        wherein: X₁ is O, N, S, SO₂, NR₁₃, C(O), or bond; Q, is        hydrogen, phenyl, 5-(2,2-difluoro-1,3-benzodioxolyl), C(O)Q₅, or        pyridyl when m and n are independently 0-2, except when one is 0        the other cannot be 0; Q₁ is OR₁₁, NR₁₁R₁₂, halo, N-morpholino,        N-piperazino-N′R₁₃, N-imidazolyl, N-pyrazolyl, N-triazolyl,        N-(4-piperidinylpiperidine), SO₂R₁₄, SOR₁₄, NHSO₂R₁₅, acetamido,        N-phthalimido, N-oxazolidino, N-imidazolino, N-benzoxazolidino,        N-pyrolidinonyl, N(N′-methylbenzimidazolino),        N,N-di(C1-C4)alkylamino(C1-C4)alkoxy, N-benzimidazolino; when m        and n are independently 0-2, but one or the other of m or n is        not 0; Q₅ is hydroxy, methoxy, amino, diethylamino,        dimethylamino; R₁₀ is hydrogen, halo, (C1-C6)alkyl; R₁₁ and R₁₂        are independently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy,        arylalkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkylmethyl,        4-(N-methylpiperidinyl), pyridyl, or R₁₁ and R₁₀ can be taken        together to form a 4, 5, 6, or 7 membered ring, or R₁₁ and R₁₂        can be taken together to form a 3, 4, 5, 6, or 7 membered ring;        R₁₃ is hydrogen, (C1-C6)alkyl, 2-methoxyphenyl, 2-pyridimidinyl;        R₁₄ is 2-pyrimidinyl, N-methyl-2-imidazolyl, 4-chlorophenyl,        2-pyridylmethyl; R₁₅ is (C1-C6)alkyl, N-methyl-4-imidazolyl; R₁₆        is hydrogen, halo, arylalkyl, aryl,        or a group of the formula:        wherein: Q₂ is hydrogen, 4-imidazolyl, or C(O)NR₂₄R₂₅ when o and        p are independently 0-2; Q₂ is OR₂₃, NR₂₄R₂₅, or N-morpholino,        when o and p are independently 0-2, but one or the other of o or        p is not 0; R₂₀ is hydrogen, or (C1-C6)alkyl; R₂, is hydrogen,        (C1-C6)alkyl, or R₂₁ and R₂₀ can be taken together to form a 4,        5, 6, or 7 membered ring; R₂₂ is hydrogen, (C1-C6)alkyl,        arylalkyl, aryl, or R₂₁ and R₂₂ can be taken together to be a 3,        4, 5, 6, 7 membered ring; R₂₃ is hydrogen or (C1-C6)alkyl; R₂₄        is hydrogen, (C1-C6)alkyl, or R₂₄ and R₂₅ can be taken together        to form a 3, 4, 5, 6, or 7 membered ring, or R₂₄ and R₂₀ can be        taken together to form a 6 or 7 membered ring; R₂₅ is hydrogen,        (C1-C6)alkyl, or acetyl,        or a group of the formula:        wherein: R₃₀ is hydrogen, or (C1-C6)alkyl; R₃₁ is hydrogen,        (C1-C6)alkyl, 2-pyridyl, pyridylmethyl, amino, or hydroxy,        or a group of the formula:        wherein: R₃₂ and R₃₃ are each independently hydrogen,        (C1-C6)alkyl, acetyl, (C1-C4)alkylsulphonyl, or R₃₂ and R₃₃ can        be taken together to form a 4, 5, 6, or 7 membered ring,        or a group of the formula:        wherein: X₂ is CH₂, O, or N; q is 2-3 except when Q₃ is a bond,        q is 0-3; Q₃ is NR₃₆R₃₇, or OR₃₈, and R₃₅ is hydrogen, or R₃₅        and Q₃ can be taken together to form a 5 membered ring; R₃₆,        R₃₇, and R₃₈ are each independently hydrogen, or (C1-C6)alkyl,        or a group of the formula:        wherein: X₃ is cyano, carboxamide, N,N-dimethylcarboxamide,        N,N-dimethylthiocarboxamide, N,N-dimethylaminomethyl,        4-methylpiperazin-1 yl-methyl or carboxylate,        or a group of the formula:        wherein: Q₆ is NR₄₁R₄₂; r is 2-3; R₄₀ is hydrogen, or        (C1-C6)alkyl; R₄₁ and R₄₂ are hydrogen, (C1-C6)alkyl, or R₄₁ and        R₄₀ can be taken together to form a 6 or 7 membered ring,        or a group of the formula:        wherein: Q₇ is hydroxy, methoxy, dimethylamino, or        N-piperidinyl; and wherein R₇ is hydrogen; benzyl; aryl; C₁-C₄        alkyls; halogen; —CO₂(C₁-C₄ alkyl); —CONR₆R₆; —C₁-C₄ alcohol;        —SO2(C1-C4 alkyl); —COR₈;        wherein R₆ is (C1-C4alkyl)R₉; R₈ is (C1-C4alkl) or        (C2-C4alkenyl); and R₉ is NR₃R₄,        wherein R₃ and R₄ are each independently (C1-C4alkyl);        and the pharmaceutically acceptable salts, esters and prodrugs        thereof.

The compounds are useful for the treatment of cancer and other diseasestates influenced by TGF beta, such as fibrosis, atherosclerosis,Alzheimer's disease, wound healing, HIV infection and restenosis, andinflammation, including, but not limited to, for example, arthritis,inflammatory bowel disease, Crohn's disease, irritable bowel syndrome,ulcerative colitis, etc., by inhibiting TGF-β in a patient in needthereof by administering said compound(s) to said patient.

DETAILED DESCRIPTION OF THE INVENTION

The general chemical terms used herein have their usual meanings. Forexample, as used herein, the term “C₁-C₄ alkyl”, alone or incombination, denotes a straight-chain or branched-chain C₁-C₄ alkylgroup consisting of carbon and hydrogen atoms, examples of which aremethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and thelike. The term “geminal dimethyl” represents two methyl groups attachedat the same substitution position. The term “C₃-C₆ cycloalkyl” refers tocyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term“spiro-fused C₃-C₆ cycloalkyl” refers to a C₃-C₆ cycloalkyl group asdefined above bonded to a carbon atom through a spiro linkage.

The term “C₁-C₄ alkoxy”, alone or in combination, denotes an alkyl groupas defined earlier, which is attached via an oxygen atom, such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, andthe like. The term “C₁-C₄ alkylthio”, alone or in combination, denotesan alkyl group as defined earlier and is attached via a sulfur atom, andincludes methylthio, ethylthio, isobutylthio, and the like.

As used herein, the term “halo” or “halogen” represents fluorine,chlorine, bromine, or iodine. The term “hydroxy,” alone or incombination, represents an —OH moiety. The term “carboxy” or “carboxyl”refers to a carboxylic acid. The term “carboxamide” refers to a carbonylsubstituted with an —NH₂ moiety. The term “oxo” refers to a carbonylgroup.

As used herein, the term “heteroaryl” means an aryl moiety, whichcontains 1-5 heteroatoms selected from O, S, and N. Examples ofheteroaryl groups include pyrrolyl, pyrazolyl, pyranyl, thiopyranyl,furanyl, imidazolyl, pyridyl, thiazolyl, triazinyl, phthalimidyl,indolyl, purinyl, and benzothiazolyl.

As used herein, the term “aryl” represents a substituted orunsubstituted phenyl or naphthyl. Aryl may be optionally substitutedwith one or more groups independently selected from hydroxy, carboxy,C₁-C₆ alkoxy, C₁-C₆ alkyl, halogen, carboxamide, trifluoromethyl,hydroxymethyl, and hydroxy(C₁-C₄)alkyl.

The term “C₃-C₈ cycloalkyl” refers to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term“optionally substituted C₃-C₈ cycloalkyl” refers to a C₃-C₈ cycloalkylas defined herein unsubstituted or substituted with one or more groupsindependently selected from hydroxy, carboxy, C₁₋₆ alkoxy, C₁₋₆ alkyl,halogen, carboxamide, trifluoromethyl, hydroxymethyl, andhydroxy(C₁-C₄)alkyl.

As used herein, the term “saturated heterocycle” is taken to be a 4-9membered ring containing nitrogen and optionally one other atom selectedfrom oxygen, nitrogen, and sulfur. The term “optionally substitutedsaturated heterocycle” is taken to be a saturated heterocycle as definedherein unsubstituted or substituted with one or more groupsindependently selected from hydroxy, carboxy, C₁₋₆ alkoxy, C₁₋₆ alkyl,halogen, carboxamide, trifluoromethyl, hydroxymethyl, andhydroxy(C₁-C₄)alkyl.

As used herein, the term “C₁-C₆ alkyl” refers to straight or branched,monovalent, saturated aliphatic chains of 1 to 6 carbon atoms andincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term “C₁-C₆alkyl” includes within its definition the terms “C₁-C₄ alkyl” and “C₁-C₃alkyl.”

“C₁-C₆ alkenyl” refers to a straight or branched, divalent, unsaturatedaliphatic chain of 1 to 6 carbon atoms and includes, but is not limitedto, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl,isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, hexylenyl.

“C₁-C₆ alkoxycarbonyl” represents a straight or branched C₁-C₆ alkoxychain, as defined above, that is attached via the oxygen atom to acarbonyl moiety. Typical C₁-C₆ alkoxycarbonyl groups includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, t-butoxycarbonyl and the like.

The term “di(C₁-C₆ alkyl)amino” refers to a group of the formula:

wherein each R group independently represents a “C₁-C₆ alkyl” group, asdefined above.

An “optionally substituted phenyl” is a phenyl ring that isunsubstituted or substituted with 1 to 5 substituents, more preferably 1to 3 substituents, for example: halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkylamino, trifluoromethyl, nitro, and cyano.

An “optionally substituted benzyl” is a benzyl ring that isunsubstituted or substituted with 1 to 5 substituents, more preferably 1to 3 substituents, for example: halo, C₁-C₆ alkyl, C₁-C₆ alkoxy,trifluoromethyl, nitro, and cyano.

“Phenoxycarbonyl” refers to the group: phenyl-O—C(O)—. “Aryl” refers toan unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms havinga single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g.,naphthyl or anthracenyl).

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1 to 5 substituents,more preferably 1 to 3 substituents, selected from the group consistingof halo, hydroxy, acetyl, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenyl, di(C₁-C₆ alkyl)amino, trifluoromethyl, trifluoromethoxy,—S(O)_(m)—(C₁-C₆ alkyl), and —S(O)_(m)-(phenyl), wherein m can be 0, 1,or 2.

“Arylalkyl” refers to aryl groups attached to alkyl groups, preferablyhaving 1 to 6 carbon atoms in the alkyl moiety and 6 to 10 carbon atomsin the aryl moiety. Such arylalkyl groups are exemplified by benzyl,phenethyl, and the like.

Unless otherwise constrained by the definition for arylalkyl, sucharylalkyl groups can be optionally substituted with 1 to 5 substituents,more preferably 1 to 3 substituents, selected from the group consistingof halo, hydroxy, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy, di(C₁-C₆alkyl)amino, trifluoromethyl, trifluoromethoxy, carbamoyl, pyrrolidinyl,—S(O)_(m)—(C₁-C₆ alkyl), and —S(O)_(m)-(phenyl), wherein m can be 0, 1,or 2. The arylalkyl groups may be optionally substituted on the arylmoiety, the alkyl moiety, or both the aryl moiety and the alkyl moiety.

The term “heterocycle” represents an unsubstituted or substituted 5- to7-membered monocyclic, or 7- to 11-membered bicyclic heterocyclic ringthat is saturated or unsaturated and that consists of carbon atoms andfrom one to five heteroatoms selected from the group consisting ofnitrogen, oxygen or sulfur, and including a bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring toanother heterocycle as defined above.

The term “heteroaryls” represents the above-defined heterocylic ringsthat are fused to a benzene ring to another heterocylce as definedabove.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocycles can be optionally substituted with 1 to 8substituents selected from the group consisting of halo, nitro, cyano,hydroxy, acetyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₁₀ cycloalkyl,optionally substituted phenyl, phenethyl, phenoxy, phenoxycarbonyl,optionally substituted benzyl, 1,1-diphenylmethyl, oxo, C₁-C₆alkoxycarbonyl, (C₁-C₆ alkoxy)C₁-C₆ alkyl-, trifluoromethyl, pyridyl,(pyrrolidinyl)C₁-C₆ alkyl-, and (pyridyl)C₁-C₆ alkyl-, di(C₁-C₆alkyl)amino, trifluoromethyl, trifluoromethoxy, —S(O)_(m), (C₁-C₆alkyl), and —S(O)_(m)-(phenyl), wherein m can be 0, 1, or 2.

Examples of such heterocycles include azepinyl, azetidinyl,benzazepinyl, benzimidazolyl, benzoazolyl, benzodioxolyl, benzodioxanyl,benzopyranyl, benzothiazolyl, benzothienyl, dihydropyrazolooxazinyl,dihydropyrazolooxazolyl, furyl, imidazolyl, imidazolinyl,imidazolidinyl, indolinyl, indolyl, isoindolinyl, isoquinolinyl,isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl,napthyridinyl, oxadiazolyl, oxazolyl, oxazolidinyl, phthalimidyl,piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolidinyl,pyrrolopyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydropyranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiazolinyl, thiazolidinyl,thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, and the like.

Preferred heterocycles include: benzodioxolyl, dihydropyrrolopyrazolyl,pyridyl, quinolinyl.

The preceding paragraphs may be combined to define additional preferredclasses of compounds.

The compounds of Formula I are useful for the treatment of disorders ofmammals, and the preferred mammal is a human.

The skilled artisan will appreciate that the introduction of certainsubstituents will create asymmetry in the compounds of Formula I. Thepresent invention contemplates all enantiomers and mixtures ofenantiomers, including racemates. It is preferred that the compounds ofthe invention containing chiral centers are single enantiomers. Thepresent invention further contemplates all diastereomers.

Compounds Exemplified in the Application Include the Following:

-   4-[2-(6-Ethyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   [2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid methyl ester,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-6-carboxylic    acid methyl ester,-   4-(5-Benzyl-2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline-7-carboxylic    acid methyl ester,-   3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-6-carboxylic    acid (2-dimethylamino-ethyl)-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-6-carboxylic    acid (2-dimethylamino-ethyl)-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid (2-dimethylamino-ethyl)-amide,-   5-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-benzofuran-2-carboxylic    acid (2-dimethyl amino-ethyl)-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid[3-(4-methyl-piperazin-1-yl)-propyl]-amide,-   4-[2-(6-Methoxy-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   4-[2-(6-Ethoxy-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   3-(4-Fluoro-phenyl)-2-(6-methoxy-pyridin-2-yl)-pyrazolo[1,5-a]pyridine,-   2-(6-Ethoxy-pyridin-2-yl)-3-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine,-   7-Benzyl-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylic    acid methyl ester,-   3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylic    acid,-   4-[2-(6-Ethylsulfanyl-pyridin-2-yl)-pyrazolo[1,5-a]-pyridin-3-yl]-quinoline,-   4-[2-(6-Phenylsulfanyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   4-[2-(6-Morpholin-4-yl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   3-(4-Fluoro-phenyl)-2-(6-methylsulfanyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine,-   3-(4-Methylsulfanyl-phenyl)-2-(6-methylsulfanyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine,-   Dimethyl-(2-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-ylsulfanyl}-ethyl)-amine,-   2-(Pyridin-2-yl)-3-(quinolin-4-yl)-pyrazolo[1,5-a]pyridine-5-carboxylic    acid dimethylamide,-   2-(Pyridin-2-yl)-3-(quinolin-4-yl)-pyrazolo[1,5-a]pyridine-6-carboxylic    acid dimethylamide,-   4-[2-(6-Vinyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,-   6-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-imidazo[1,2-a]pyridin-2-yl-amine,-   6-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-1H-benzoimidazol-2-yl-amine,-   [3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-6-yl]-methanol,-   6-Allyloxymethyl-3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid(3-pyrrolidin-1-yl-propyl)-amide,-   3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-propionamide,-   3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-N-(3-pyrrolidin-1-yl-propyl)-propionamide,-   N-(2-Dimethylamino-ethyl)-3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-propionamide,-   2-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]pyridine-5-carboxylic    acid (3-dimethylamino-propyl)-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid (2-hydroxy-ethyl)-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid hydrazide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid (3-hydroxy-propyl)-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid methylamide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid (3-ethoxy-propyl)-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid (3-morpholin-4-yl-propyl)-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid (3-imidazol-1-yl-propyl)-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid (3-dimethylamino-propyl)-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid[2-(2-methoxy-phenyl)-ethyl]-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid (2-morpholin-4-yl-ethyl)-amide,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic    acid amide,-   Dimethyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}-propyl)-amine,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-7-(2-morpholin-4-yl-ethoxy)-quinoline,-   Diisopropyl-(2-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}-ethyl)-amine,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-7-(2-pyrrol-1-yl-ethoxy)-quinoline,-   Dimethyl-(1-methyl-2-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}ethyl)-amine,-   Methyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl-oxy}-propyl)-amine,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-7-(2-piperidin-1-yl-ethoxy)-quinoline,-   Diethyl-(2-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}-ethyl)-amine,-   Dimethyl-{3-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   7-(2-Morpholin-4-yl-ethoxy)-4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline,-   Diisopropyl-{2-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-ethyl}-amine,-   4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-7-(3-morpholin-4-yl-propoxy)-quinoline,-   1-(3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-yl]-quinolin-7-yloxy}-propyl)-1,3-dihydro-benzoimidazol-2-one-   3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-propionic    acid methyl ester,-   Diethyl-{3-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   Ethyl-methyl-{3-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-propyl}-amine,-   4-(2-Pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-7-(3-pyrrolidin-1-yl-propoxy)-quinoline,-   7-(3-Piperidin-1-yl-propoxy)-4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline,-   Diethyl-{2-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-ethyl}-amine,-   Dimethyl-{2-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-ethyl}-amine,    and the pharmaceutically acceptable salts, esters and prodrugs    thereof.

The compounds exemplified above are merely representative of theinvention and are not limiting in any fashion.

The compounds of the present invention can be prepared by a variety ofprocedures, some of which are illustrated in the Schemes below. It willbe recognized by one of skill in the art that the individual steps inthe following schemes may be varied to provide the compounds of FormulaI. Some of these variations are discussed below.

The particular order of steps required to produce the compounds ofFormula I is dependent upon the particular compound being synthesized,the starting compound, and the relative lability of the substitutedmoieties. Some substituents have been eliminated in the followingschemes for the sake of clarity, and are not intended to limit theteaching of the schemes in any way.

Scheme I, depicts a cyclization of optionally substituted1-amino-pyridinium salts of formula (2), and optionally substitutedethanones of formula (1) in the formation of Formula I. Cyclizationreaction of the optionally substituted ethanones of formula (1) with the1-amino-pyridinium salt, in which the counter-anion, Z, can be a halogenor a trialkyl-benzenesulfonate, are generally done with an organic base,such as triethylamine, DBU, or preferably diisopropylethylamine, in asuitable solvent such as ethanol under elevated temperatures. Theproduct of Formula I can be isolated and purified by techniques wellknown in the art, such as precipitation, filtration, extraction,evaporation, trituration, chromatography, and recrystallization.

Scheme II depicts an acylation of an appropriate aromatic and/orheteroaromatic compound of formula (3) and an appropriate carbonylcompound of formula (5) to give a compound of formula (1). The aromaticand/or heteroaromatic compounds of formula (3) are commerciallyavailable or can be produced by methods known in the art. The acylationof formula (3) requires that R8, of formula (5), be a suitable leavinggroup, such as C1-C6 alkoxy, disubstituted amino, halo, C1-C6 thioether,preferably disubstituted amino. The reaction is typically carried out inthe presence of a suitable base that can create an anion of the compoundof formula (3), such as lithium diisopropylamide, potassiumbis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, sodium hydride, lithium hydride, potassiumhydride, sodium alkoxides (sodium methoxide, or sodium ethoxide) orpotassium alkoxides (potassium methoxide, or potassium ethoxide), withpotassium bis(trimethylsilyl)amide being the preferred base. Generally,the reaction is carried out in suitable solvents, such astetrahydrofuran and toluene or a combination of such, at temperatures ofabout −78° C. to ambient temperature. The product, formula (1), can beisolated and purified by techniques well known in the art, such asprecipitation, filtration, extraction, evaporation, trituration,chromatography, and recrystallization. Another variation of theacylation is to use a nitrile compound of formula (4) in place of thearomatic- or heteroaromatic-methyl compounds of formula (3). Theintermediate, cyanoketone, can be transformed to formula (1) byhydrolysis of the nitrile group and then subsequent decarboxylation.Generally, the cyanoketone is dissolved in a hydrogen halide acidsolution, preferably hydrogen chloride. The reaction is carried out attemperatures of about ambient to refluxing for about 24 hours. This typeof reaction is well known and appreciated in the art (Larock, R. C.,Comprehensive Organic Transformations, copyright 1989, VCH, pp 993).Compounds of formula (4) can be acquired by treatment of an appropriatesubstituted aromatic- or heteroaromatic-methyl group with a halogenatingreagent, such as N-halosuccinimides, preferably N-bromosuccinimide incarbon tetrachloride and subsequently reacting thearomatic-halomethylene intermediate with a nitrile source, such aslithium cyanide, potassium cyanide, or trimethylsilyl cyanide,preferably sodium cyanide. The reaction is carried out at ambienttemperatures for about 24 hours to afford the acetonitrile compounds offormula (4), (Larock, R. C., Comprehensive Organic Transformations,copyright 1989, VCH, pp 313; Eur. J. Org. Chem. 1999, 2315-2321).

In Scheme I, optionally substituted I-amino-pyridium salts of formula(2) are employed in the formation of Formula I. These salts are eithercommercially available or may be prepared by generally combining theappropriate substituted pyridine of formula (7) with atrialkyl-benzenesulfononylhydroxylamine preferablyO-(2,4,6-trimethyl-benzenesulfonyl)-hydroxylamine in a suitable solventsuch as diciforomethane. These salts can be isolated and purified byprecipitation with a nonpolar solvent such as hexanes.

To further elaborate substitution for compounds of Formula I at the R2functionality, Scheme IV can be followed. Scheme IV depicts theformation of the pyrazolopyridine nucleus by cyclization of anappropriate substituted propynoic carboxyl-ester, followed by a typicalhydrolysis of the ester (Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) Ed., copyright 1999, John Wiley & Sons, pp1959-1968) to the carboxylic acid, and a halodecarboxylation Referenceto give formula (9), where X is a halogen. The cyclization procedure issimilar to the one previously described in Scheme I, with the exceptionthat the preferable base is DBU and the solvent should be acetonitrile.With a halogen at the C3 position of the pyrazolopyridine ring acoupling reaction with a boronic acid derivative of formula (10) can beconducted. This type of coupling reaction is well known in the art(Larock, R. C., Comprehensive Organic Transformations, 2^(nd) Ed.,copyright 1999, John Wiley & Sons, pp 104-107).

Scheme V, depicts a carbonylation reaction for the formation ofcompounds of formula (5) and (13), where R8 is a suitable leaving groupsuch as C1-C6 alkoxy, disubstituted amino, halo, C1-C6 thioether,preferably C1-C6 alkoxy. Compounds of formula (11) and (12) are used inthe formation of formula (5) and (13), respectively. The carbonyl groupof formula (5) and (13) can further undergo a synthetic transformationto interconvert between the leaving groups R8, where R8 is previouslydescribed. The Y group can be an aromatic or heteroaromatic halide andthe reaction can be carried out in the presence of carbon monoxide, asuitable nucleophile, such as an amine or an alcohol, with a palladium(0) or palladium (II) catalyst, such as 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II): dichloromethane,tetrakis(triphenylphosphine)-palladium(0),bis(triphenylphosphine)palladium (II) chloride or palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0),tris-(benzylideneacetone)dipalladium(0), palladium dichloride, palladiumbis(trifluoroacetate), or preferably 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II):dichloromethane. All reagents of thereagents are combined in a suitable solvent, typically terahydrofuran,toluene or ethylene glycol dimethyl ether, stirred at temperatures ofabout 0 to 80° C. All products can be isolated and purified bytechniques described above.

Scheme VI depicts the manipulation of hydroxy-aryl compounds of formula(15) for further alkylations and transformations to enable the scope ofthis invention, where the R group(s) are previously described.Representative conversions are shown in Scheme VI.

Scheme VI, depicts the deprotection of a protected aromatic-hydroxygroup of formula (14) to give a compound of formula (15), where the “Pg”can be an alkoxide. The deprotection is well known and appreciated inthe art (Greene T. W., Wuts, P. G. M. Protective Groups in OrganicSynthesis, copyright 1991, John Wiley and Sons, Inc., pp146-149). Theproduct of formula (15) can be isolated and purified by techniquespreviously described.

Scheme VI also depicts the transformation of an aryl ether compound offormula (15) to give the compounds of Formula (I). The formation of anaryl ether is well known and appreciated in the art (March, J., AdvancedOrganic Chemistry, copyright 1985, John Wiley and Sons, Inc., pp342-343,589. and Mundy, B. P., Ellerd, M. G. Name Reactions and Reagents inOrganic Synthesis, copyright 1988, John Wiley and Sons, Inc., pp 242,530; Sawyer, J. S., Schmittling, E. A., Palkowitz, J. A., Smith, III, W.J., J. Org. Chem., 1998, 63, 6338-6343). The products can be isolatedand purified by techniques described above.

Scheme VI furthermore depicts an alkyation of a compound of formula (15)to give a variably substituted compound of formula (16), where theleaving group(s) “Lg” and “Lg” can include such leaving groups, but arenot limited to, halides, oxonium ions, alkyl perchlorates,ammuonioalkanesulfonate esters, alkyl fluorosulfonates, nonaflates,tresylates, triflates, and sulfonic esters, preferably the mesylate ortosylate, given “Lg” and “Lg” are not the same group. Typically, theappropriate compound of formula (15) is reacted with a suitable basethat can form the anion of the phenol, such as lithium carbonate, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydride,lithium hydride, potassium hydride, with cesium carbonate being thepreferred base, in the presence of a compound of formula (17). Thereaction is carried out in a suitable solvent, such as tetrahydrofuran,dimethylsulfoxide, dimethyl acetamide or toluene, or preferablyN,N-dimethylformamide at temperatures of about 0 to 100° C. The productscan be isolated and purified by techniques described above.

Finally, Scheme VI, depicts the nucleophilic substitution of leavinggroup “Lg”, by a nucleophile to form a compound of the formula (16).Nucleophilic substitution is well known and appreciated in the art(March, J., Advanced Organic Chemistry, copyright 1985, John Wiley andSons, Inc., pp 255-446). Typically, the compound of formula (16) isreacted with a nucleophile of formula (17), which is typically, but notlimited to, primary amines, secondary amines, alcohols or thiols. Thereaction is carried out in a suitable solvent, such as tetrahydrofuran,dimethylsulfoxide, dimethyl acetamide or toluene, or preferablyN,N-dimethylformamide at temperatures of about 0 to 100° C. The productscan be isolated and purified by techniques described above.

A skilled artisan can appreciate several transformations that can beapplied to the synthetic process for production of useful and reactiveintermediates. Further elaboration can be completed by transformation ofthe appropriate functional groups, such as trans-formation of acarboxylester to an amide, halogen alkoxy exchange (Larock, R. C.,Comprehensive Organic Transformations, 2^(nd) Ed., copyright 1999, JohnWiley & Sons, pp 893-894), hydrolysis of a carboxylester (Larock, R. C.,Comprehensive Organic Transformations, 2^(nd) Ed., copyright 1999, JohnWiley & Sons, pp 1959-1968), palladium promoted additions (Larock, R.C., Comprehensive Organic Transformations, 2^(nd) Ed., copyright 1999,John Wiley & Sons, pp 1685-1687), O-alkylations (Larock, R. C.,Comprehensive Organic Transformations, 2^(nd) Ed., copyright 1999, JohnWiley & Sons, pp 890-893) and a nucleophilic exchange ofaromatic-halogens (Larock, R. C., Comprehensive Organic Transformations,2^(nd) Ed., copyright 1999, John Wiley & Sons, pp 779-780). These typesof transformations of functional groups are well known and appreciatedin the art.

A skilled artisan would also appreciate that amine containingintermediates can be protected with various protecting groupssuch as aformyl group, acetyl, or preferably a tert-butoxycarbonyl moiety.Techniques for the introduction of these groups are well known to theskilled artisan. The skilled artisan will appreciate that thenitrogen-protecting groups may be removed at any convenient point in thesynthesis of the compounds of the present invention. Methods offormation and removal of an amino-protecting group are well known in theart (for example, see: T. W. Greene, “Protective Groups in OrganicSynthesis,” John Wiley and Sons, New York, N.Y., 1991, Chapter 7).

The skilled artisan would appreciate that appropriate leaving groups forthe hydroxy intermediates could include halides, oxonium ions, alkylperchlorates, ammonio-alkanesulfonate esters, alkyl fluorosulfonates,nonaflates, tresylates, triflates, and sulfonic esters, preferably themesylate or tosylate. Techniques for the introduction of these groupsare well known to the skilled artisan. (See for example: March,“Advanced Organic Chemistry,” John Wiley and Sons, New York, N.Y., 1992,pg. 352-362). The hydroxy compound is then dissolved in an appropriatesolvent, such as tetrahydrofuran, diethyl ether or N,N-dimethylformamideand is reacted with a strong base, such as potassium hydride or sodiumhydride. The reaction is conducted under nitrogen at about 0° C. andstirred for 30-120 minutes. These compounds can be isolated and purifiedby standard techniques.

Many of the compounds of the present invention are not only inhibitorsof TGF-beta, but are also usefull intermediates for the preparation ofadditional compounds of the present invention. For example, secondaryamines may be acylated, alkylated or coupled with simple carboxylicacids or amino acids under standard conditions. Furthermore, estermoieties may be reduced to the corresponding alcohols. These alcoholsmay then be activated and displaced by a number of nucleophiles toprovide other compounds of the invention. The skilled artisan will alsoappreciate that not all of the substituents in the compounds of FormulaI will tolerate certain reaction conditions employed to synthesize thecompounds. These moieties may be introduced at a convenient point in thesynthesis, or may be protected and then deprotected as necessary ordesired. Furthermore, the skilled artisan will appreciate that in manycircumstances, the order in which moieties are introduced is notcritical.

The following preparations and examples further illustrate thepreparation of compounds of the present invention and should not beinterpreted in any way as to limit the scope. Those skilled in the artwill recognize that various modifications may be made while notdeparting from the spirit and scope of the invention. All publicationsmentioned in the specification are indicative of the level of thoseskilled in the art to which this invention pertains.

The terms and abbreviations used in the instant Preparations andExamples have their normal meanings unless otherwise designated. Forexample “° C.”, “N”, “mmol”, “g”, “mL”, “M”, “HPLC”, “IR”, “MS(FD)”,“MS(IS)”, “MS(FIA)”, “MS(FAB)”, “MS(EI)”, “MS(ES)”, “IN”, and “¹H NMR”,refer to degrees Celsius, normal or normality, millimole or millimoles,gram or grams, milliliter or milliliters, molar or molarity, highperformance liquid chromatography, infrared spectrometry, fielddesorption mass spectrometry, ion spray mass spectrometry, flowinjection analysis mass spectrometry, fast atom bombardment massspectrometry, electron impact mass spectrometry, electron spray massspectrometry, ultraviolet spectrometry, and proton nuclear magneticresonance spectrometry, respectively. In addition, the absorption maximalisted for the IR spectra are only those of interest and not all of themaxima observed.

Preparation 1 2-Ethynyl-6-methyl-pyridine

2-Bromo-6-methylpyridine (0.5 g, 2.9 mmol) and trimethylsilylacetylene(0.29 g, 2.9 mmol) in Et₃N (15 mL) is purged with argon. Then CuI (11mg, 0.06 mmol) and (PPh₃)₂PdCl₂ (42 mg, 0.06 mmol) are added and thereaction stirred under argon at room temp for 2 hours. The solvent isremoved in vacuo and the residue diluted in EtOAc (50 mL) and water (50mL). The organic is separated and washed with brine. The solvent isremoved to afford a dark oil. This oil is diluted in MeOH (50 mL) andtreated with a 1 N NaOH solution (10 mL) and stirred for 3 hours at roomtemp. The aqueous is then acidified to pH=4 with 1 N HCl and extractedwith dichloromethane. The solvent is removed in vacuo to afford 1.16 g(24%) as a light yellow oil used as is in following reactions. ¹H NMR(CDCl₃) δ: 7.54 (t, 1H), 7.29 (d, 1H), 7.12 (d, 1H), 3.12 (s, 1H), 2.55(s, 1H). MS ES⁺ m/e 118.1 (M+1).

By method in PREPARATION 1 the following compounds were synthesized:Product PREP (Chemical Starting Starting Physical Com- # Name) MaterialA Material B Data ments 2 2- 2- MS ES⁺ m/e Ethynyl- Bromopyridine 103.9(M + 1). pyridine 3 2-Ethyl-6- 2-Bromo-6- MS ES⁺ m/e ethynyl-ethylpyridine 133.0 (M + 1). pyridine

Preparation 4 (6-Methyl-pyridin-2-yl)-propynoic acid ethyl ester

A solution of 2-Ethynyl-6-methyl-pyridine (0.5 g, 4.3 mmol) in THF (20in L) is cooled to −78° C. and treated with 1.6 M n-butyllithium inhexanes (2.9 mL, 4.7 mmol) and stirred for 0.5 hours. This solution isthen treated with ethyl chloroformate (2.85 mL, 30 mmol) and stirred for3 hours while the solution warms to room temperature The reaction isdiluted with saturated aqueous ammonium chloride and extracted withEtOAc. The solvent is concentrated to afford 0.67 g (83%) of desiredproduct as a light yellow oil. UV (95% EtOH) λ_(max) 286 nm (ε 10977),238 nm (ε 9757). TOF MS ES⁺ exact mass calculated for C₁₁H¹¹NO₂ (p+1):M/z=190.0868. Found: 190.0864.

By method in PREPARATION 4 the following compounds were synthesized:Product PREP (Chemical Starting Starting Com- # Name) Material AMaterial B Physical Data ments 5 Pyridin-2-yl- 2-Ethynyl- MS ES⁺ m/epropynoic acid pyridine 176.2 (M + 1). ethyl ester (Prep. 2) 6 (6-Ethyl-2-Ethyl-6- MS ES⁺ m/e pyridin-2-yl)- ethynyl- 204.1 (M + 1). propynoicacid pyridine ethyl ester (Prep. 3)

Preparation 72-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-carboxylic acidethyl ester

A solution of (6-methyl-pyridin-2-yl)-propynoic acid ethyl ester (0.62g, 3.3 mmol) and 1-aminopyridinium iodide (0.8 g, 3.6 mmol) inacetonitrile (15 mL) is treated with DBU (0.5 mL, 3.3 mmol) and heatedto reflux for 0.5 hours. The reaction is concentrated to a dark solidand purified by silica gel column chromatography (1:1 hexane/ethylacetate) to afford 0.224 g (24%) of desired product as a yellow solid.MS ES⁺ m/e 282.2 (M+1). UV (95% EtOH) λ_(max) 275 nm (ε 13005), 234 nm(ε 26550), 225 nm (ε 26057). TOF MS ES⁺ exact mass calculated forC₁₁H₁₁NO₂ (p+1): m/z=282.1243. Found: 282.1244. Anal. Calcd forC₁₆H₁₅N₃O₂: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.04; H, 5.28; N,14.65. PREP Product Starting Starting # (Chemical Name) Material AMaterial B Physical Data Comments 8 2-(6-Methyl- (6-Methyl- 1-Amino-3-¹H NMR of When treated pyridin-2-yl)-6- pyridin-2-yl)- phenyl Isomer 1with 3- phenyl- propynoic pyridinium (CDCl₃) substituted pyrazolo[1,5-acid ethyl δ 8.79(s, 1H), aminated a]pyridine-3- ester (Prep. 4) 8.27(d,1H), pyridine, carboxylic acid 7.73-7.59(m, reaction gave ethyl ester5H), 7.53-7.42 mixture of (Isomer 1) (m, 3H), 7.23 products with 4 and(d, 1H), 4.31 or 6 substitution 2-(6-Methyl- (q, 2H), 2.68pyridin-2-yl)-4- (s, 3H), 1.30(t, phenyl- 3H) and pyrazolo[1,5- ¹H NMRof a]pyridine-3- Isomer 2 carboxylic acid δ 8.54(d, 1H), ethyl ester7.74(d, 1H), (Isomer 2) 7.65(t, 1H), 7.44(m, 5H), 7.16(m, 2H), 6.96(t,1H), 3.69(q, 2H), 2.57(s, 3H), 0.92(t, 3H) 9 6- (6-Methyl- 1-Amino-3- MSES⁺ m/e When treated Methanesulfonyl- pyridin-2-yl)- methanesulfon-360.1 (M + 1). with 3- 2-(6-methyl- propynoic yl pyridinium substitutedpyridin-2-yl)- acid ethyl iodide aminated pyrazolo[1,5- ester (Prep. 4)pyridine, a]pyridine-3- reaction gave carboxylic acid mixture of ethylester products with 4 and or 6 4- substitution. Methanesulfonyl- Mixturecould 2-(6-methyl- be separated by pyridin-2-yl)- chromatographypyrazolo[1,5- a]pyridine-3- carboxylic acid ethyl ester 102-Pyridin-2-yl- Pyridin-2-yl- 1- MS ES⁺ m/e pyrazolo[1,5- propynoicAminopyridini- 268.1 (M + 1). a]pyridine-3- acid ethyl um iodidecarboxylic acid ester (Prep. 5) ethyl ester 11 2-(6-Ethyl-pyridin(6-Ethyl- 1- MS ES⁺ m/e 2-yl)-pyrazolo[1,5- pyridin-2-yl)-Aminopyridini- 296.1 (M + 1). a]pyridine-3- propynoic um iodidecarboxylic acid acid ethyl ethyl ester ester (Prep. 6)

Preparation 122-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid

A solution of2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-carboxylic acidethyl ester (0.18 g, 0.6 mmol) in EtOH (10 mL) is treated with a 2N NaOHsolution (3 mL) and refluxed for 3 hours. The reaction is concentratedto a yellow solid and diluted with 1N HCl (30 mL). The aqueous isextracted with CH₂Cl₂ (3×10 mL) and the organic solution dried overNa₂SO₄. The solution is filtered and the solvent removed in vacuo toafford 0.152 g (94%) of desired product as a white solid. MS ES⁺ m/e254.1 (M+1). UV (95% EtOH) λ_(max) 284 nm (ε 23625), 244 nm (ε 24036).TOF MS ES⁺ exact mass calculated for C₁₄H₁₁N₃O₂ (p+1): m/z=254.0930.Found: 254.0919. Anal. Calcd for C₁₄H₁₁N₃O₂: C, 66.40; H, 4.38; N,16.59. Found: C, 66.22; H, 4.42; N, 16.25. PREP Product StartingMaterial Starting # (Chemical Name) A Material B Physical Data Comments13 2-(6-Methyl- 2-(6-Methyl- MS ES⁻ m/e Product was pyridin-2-yl)-6-pyridin-2-yl)-6- 328.1 (M − 1). isolated as a phenyl- phenyl- mixturepyrazolo[1,5- pyrazolo[1,5- a]pyridine-3- a]pyridine-3- carboxylic acidcarboxylic acid and ethyl ester 2-(6-Methyl- (Isomer 1) and 2-pyridin-2-yl)-4- (6-Methyl- phenyl- pyridin-2-yl)-4- pyrazolo[1,5-phenyl- a]pyridine-3- pyrazolo[1,5- carboxylic acid a]pyridine-3-carboxylic acid ethyl ester(Isomer 2) (Prep. 8) 14 6- PREP. 9 MS ES⁺ m/eMethanesulfonyl- 332.1 (M + 1), 2-(6-methyl- MS ES⁻ m/e pyridin-2-yl)-330.2 (M − 1). pyrazolo[1,5- a]pyridine-3- carboxylic acid 152-Pyridin-2-yl- PREP. 10 MS ES⁻ m/e pyrazolo[1,5- 238 (M − 1).a]pyridine-3- carboxylic acid 16 2-(6-Ethyl-pyridin- PREP. 11 MS ES⁻ m/e2-yl)-pyrazolo[1,5- 266.1 (M − 1). a]pyridine-3- carboxylic acid

Preparation 17 3-Bromo-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine

A solution of2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid(0.92 g, 3.6 mmol), sodium bicarbonate (1.04 g, 12.4 mmol), andN-bromosuccinimide (0.71 g, 4.0 mmol) in DMF (25 mL) is stirred for 2hours at room temperature. The reaction is then diluted with water (50mL) and extracted with EtOAc (3×15 mL). The organic layer is washed withbrine and dried over sodium sulfate. The solvent is removed in vacuo toafford 0.91 g (87%) of desired product as a dark green solid. UV (95%EtOH) 4, nm (ε 12089), 233 nm (ε 21813). TOF MS ES⁺ exact masscalculated for C₁₃H₁₀BrN₃ (p+1): m/z=288.0136. Found: 287.0058. Anal.Calcd for C₁₃H₁₀BrN₃: C, 54.19; H, 3.50; N, 14.58. Found: C, 54.10; H,3.60; N, 14.48. Product PREP (Chemical Starting Material Starting #Name) A Material B Physical Data Comments 18 3-Bromo-2-(6- 2-(6-Methyl-MS ES⁺ m/e Mixture was methyl- pyridin-2-yl)-6- 364.1, 366.1 separatedby pyridin-2-yl)- phenyl- (M + 1). Silica Gel 6-phenyl- pyrazolo[1,5-chromatography: pyrazolo[1,5- a]pyridine-3- (hexanes, a]pyridinecarboxylic acid EtOAc) and 2-(6-Methyl- pyridin-2-yl)-4- phenyl-pyrazolo[1,5- a]pyridine-3- carboxylic acid (Prep. 13) 19 3-Bromo-2-(6-2-(6-Methyl- MS ES⁺ m/e Mixture was methyl- pyridin-2-yl)-6- 364.1,366.1. separated by pyridin-2-yl)- phenyl- (M + 1). chromatography,4-phenyl- pyrazolo[1,5- as above pyrazolo[1,5- a]pyridine-3- a]pyridinecarboxylic acid and 2-(6-Methyl- pyridin-2-yl)-4- phenyl- pyrazolo[1,5-a]pyridine-3- carboxylic acid (Prep. 13) 20 3-Bromo-6- 6- Exact Massmethanesulfonyl- Methanesulfonyl- calculated 2-(6-methyl- 2-(6-methyl-365.9912, pyridin-2-yl)- pyridin-2-yl)- found pyrazolo[1,5-pyrazolo[1,5- 365.9923 a]pyridine a]pyridine-3- carboxylic acid (Prep.14) 21 3-Bromo-2- 2-Pyridin-2-yl- MS ES⁺ m/e pyridin-2-yl- pyrazolo[1,5-273.9, 275.9 pyrazolo[1,5- a]pyridine-3- (M + 1). a]pyridine carboxylicacid (Prep. 15) 22 3-Bromo-2-(6- 2-(6-Ethyl- MS ES⁺ m/e ethyl-pyridin-2-pyridin-2-yl)- 302.0, 304.0 yl)-pyrazolo[1,5- pyrazolo[1,5- (M + 1).a]pyridine a]pyridine-3- carboxylic acid (Prep. 16)

Preparation 23 3-Methanesulfonyl-pyridine

To a solution of 3-bromopyridine (20 g, 127 mmol) in THF (200 ml) atroom temperature is added a solution of 2M isopropylmagnesium chloridein THF (64 ml, 127 mmol). The resulting mixture is stirred for 2 hours,treated with triethylamine (20 ml), immediately followed bymethanesulfonylchloride (10 ml, 127 mmol) and the resulting mixturestirred for 18 hours at room temperature. The mixture is diluted withwater (200 ml) and extracted with EtOAc (3×100 ml). The mixture isconcentrated in vacuo and purified on Silica gel (eluting with 50/50Hexane/EtOAc). ¹H-NMR (CDCl₃) δ: 9.17 (s, 1H), 8.90 (d, 1H), 8.25 (dd,1H), 7.55 (m, 1H), 3.12 (s, 3H).

Preparation 24 6-Ethoxy-4-methyl-quinoline

4-Ethoxyaniline (15 g, 109 mmol) in dissolved in dioxane (1L) and cooledto 0° C. in an ice bath. To this mixture is added H₂SO₄ (12 mL, 219mmol) dropwise with stirring and heating at 100° C. Water (2 mL) isadded followed by methyl vinyl ketone (13 mL, 163 mmol, in 125 mL ofdioxane) dropwise over 2 hours. The mixture is heated for 1 hour afteraddition and then cooled. To the residue is added 1.5 eq of 1M aqueousNa₂CO₃ until the pH is 8. The organic layer is separated, condensed toan oil, and purified on silica gel (eluting with 50/50 hexane/EtOAc).

The desired product is isolated as a solid 6 g (30%). TOF MS ES⁺ (M+1)188.1079.

Preparation 252-(6-Ethoxy-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-ethanone

To a solution of 6-ethoxy-4-methyl-quinoline (360 mg, 2.0 mmol) in THFat −78° C. add 1.5M lithium diisopropylamide (4.6 ml, 7.0 mmol) dropwiseand stir for 1 hour. 6-Methyl-pyridine-2-carboxylic acidmethoxy-methyl-amide (430 mg, 2.4 mmol) is then added, and the mixturestirred for 30 minutes at −78° C. before quenching with 1N HCl (5 ml).Neutralize with saturated aqueous NaHCO₃ and extract with EtOAc (3×50ml). The organic phase is then dried with MgSO₄ and concentrated invacuo. The crude product was chromatographed on silica gel (elute with50/50 Hexane/EtOAc) to give 120 mg (20%) of the title compound. MS ES⁺m/e 307.1 (M+1).

Preparation 26 4-Benzyl-pyridin-1-yl-ammonium2,4,6-trimethyl-benzenesulfonate

A solution of 4-benzyl pyridine (0.6 g, 3.5 mmol) in methylene chloride(5 ml) is cooled with ice bath. Freshly preparedO-(2,4,6-trimethyl-benzenesulfonyl)hydroxylamine (0.92 g, 4.2 mmol) inmethylene chloride (5 ml) is added dropwise with stirring. The ice bathis removed and the mixture stirred for 1 hour, then concentrated invacuo. The residue is dissolved in methylene chloride and precipitatedwith hexanes. The hexane layer is decanted. Concentration provides 1.0 g(62%) of the title compound as a viscous oil.

¹H NMR (CD₃OD) δ 8.63-8.53 (m, 2H), 7.84-7.71 (m, 2H), 7.41-7.22 (m,5H), 6.85 (s, 2H), 4.21 (s, 2H), 2.60 (s, 6H), 2.22 (s, 3H).

By the method of PREPARATION 26 the following compounds were prepared:Prep. # Product Name Physical Data 27 1-Amino-3-phenyl-pyridinium-2,4,6-¹H-NMR(CDCl₃): δ 9.24(s, 1H), 9.01 trimethyl-benzenesulfonic acid anion(d, 1H, J=4Hz), 7.97(d, 1H, J=2Hz), 7.68(t, 1H, J=2Hz), 7.56(d, 2H,J=4Hz), 7.38(m, 2H), 6.79(s, 2H), 2.63(s, 6H), 2.19(s, 3H). 281-Amino-4-phenyl-pyridinium-2,4,6- ¹H-NMR(CDCl₃): δ 8.97(d, 2H,trimethyl-benzenesulfonic acid anion J=4Hz), 8.04(d, 2H, J=4Hz), 7.72(d,2H, J=6Hz), 7.26(m, 3H), 2.81(s, 2H), 2.64(s, 6H), 2.20(s, 3H). 291-Amino-3-methanesulfonyl- ¹H-NMR(CDCl₃): δ 9.30(s, 1H), 8.97pyridinium-2,4,6-trimethyl- (d, 1H), 8.72(d, 1H), 8.16(t, 1H), 6.88benzenesulfonic acid anion (s, 2H), 2.61(s, 6H), 2.37(s, 3H). 301-Amino-3-methoxycarbonyl- ¹H-NMR(CDCl₃): δ 9.43(s, 2H), 8.40pyridinium-2,4,6-trimethyl- (d, 1H), 7.78(t, 1H), 6.82(s, 2H), 3.93benzenesulfonic acid anion (s, 3H), 2.63(s, 6H), 2.24(s, 3H) 314-Methoxycarbonyl-pyridin-1-yl- ¹H NMR(CD₃OD): δ 8.84-8.79(m, ammonium2,4,6-trimethyl- 2H), 8.39-8.31(m, 2H), 6.84(s, 2H), benzenesulfonate4.01(s, 3H), 2.59(s, 6H), 2.22(s, 3H) 32 3-Ethoxycarbonyl-pyridin-1-yl-¹H NMR(CD₃OD): δ 9.24(s, 1H), ammonium 2,4,6-trimethyl- 8.09-8.85(m,1H), 8.75-8.66(m, 1H), benzenesulfonate 8.10-8.01(m, 1H), 6.85(s, 2H),4.53- 4.43(m, 2H), 2.61(s, 6H), 2.22(s, 3H), 1.48-1.36(m, 3H) 331-Amino-3-iodo-pyridinium-2,4,6- ¹H-NMR(CDCl₃): δ 9.06(s, 1H), 8.71trimethyl-benzenesulfonic acid anion (d, 1H), 8.57(d, 1H), 7.67(t, 1H),6.86 (s, 2H), 2.61(s, 6H), 2.23(s, 3H).

Preparation 34 2-(4-Fluorophenyl)-1-pyridin-2-yl-ethanone

Combine a solution of 4-fluorophenylacetonitrile (1.00 g, 7.4 mmol) andethyl picolinate (1.12 g, 7.4 mmol) in absolute ethyl alcohol (15 mL)under N₂ with 21 wt % sodium ethoxide solution in denatured ethylalcohol (4.2 mL, 11.1 mmol) and heat to reflux for 2 hours, then pouronto ice. Adjust the pH to 4 with concentrated hydrochloric acid andcollect the precipitate by vacuum filtration. Dissolve the residue in48% aqueous hydrobromic acid (25 mL) and heat to reflux for 2 hours.Pour the solution onto ice and adjust the pH to 7 with 5N aqueous sodiumhydroxide solution. Extract the aqueous solution three times withCH₂Cl₂. Combine the organic extracts, dry (Na₂SO₄), filter, andconcentrate in vacuo to afford the title compound 668 mg (42%) as abrown amorphous solid. MS FAB⁺ m/z=216.1

By the method of PREPARATION 34 the following compounds were prepared:Prep. # Product Name Physical 35 1-(6-Ethyl-pyridin-2-yl)-2-(4-¹H-NMR(CDCl₃) δ: 7.84(d, 1H), 7.72(t, fluoro-phenyl)-ethanone 1H),7.34-7.31(m, 3H), 7.09-6.96(m, 2H), 4.50(s, 2H), 2.90(q, 2H), 1.37(t,3H) 36 2-(4-Fluoro-phenyl)-1-(6- ¹H-NMR(CDCl₃) δ: 7.85(d, 1H), 7.72(t,propyl-pyridin-2-yl)-ethanone 1H), 7.31(m, 3H), 7.00(m, 2H), 4.51(s,2H), 2.85(t, 2H), 1.83(m, 2H), 1.00(t, 3H) 371-(6-Ethyl-pyridin-2-yl)-2-(4- MS ES⁺ m/e 294.1 (M + 1).fluoro-naphthalen-1-yl)- ethanone 38 2-(4-Fluoro-phenyl)-1-(6- MS ES⁺m/e 230.09 (M + 1). methyl-pyridin-2-yl)-ethanone 392-(4-Methoxy-phenyl)-1- MS ES⁺ m/e 228.09 (M + 1). pyridin-2-yl-ethanone40 1-Pyridin-2-yl-2-(4- MS ES⁺ m/e 266.07 (M + 1).trifluoromethyl-phenyl)- ethanone 41 2-(3-Chloro-4-fluoro-phenyl)- ¹HNMR(CDCl₃) δ 7.86-7.83(m, 1H), 7.73- 1-(6-methyl-pyridin-2-yl)- 7.71(m,1H), 7.42-7.33(m, 2H), 7.26-7.04 ethanone (m, 2H), 4.49(s, 2H), 2.65(s,3H). 42 1-(6-Methyl-pyridin-2-yl)-2- ¹H NMR(CDCl₃) δ 7.87-7.85(m, 1H),7.75- (2,4,5-trifluoro-phenyl)- 7.70(m, 1H), 7.37-7.34(m, 1H), 7.15-7.07ethanone (m, 1H), 6.98-6.89(m, 1H), 4.55(s, 2H), 2.64(s, 3H) 432-(4-Fluoro-3-trifluoromethyl- ¹H NMR(CDCl₃) δ 7.86-7.84(m, 1H), 7.74-phenyl)-1-(6-methyl-pyridin-2- 7.62(m, 2H), 7.53-7.49(m, 1H), 7.36-7.33yl)-ethanone (m, 1H), 7.16-7.10(m, 1H), 4.55(s, 2H), 2.65(s, 3H) 441-(6-Chloro-pyridin-2-yl)-2-(4- ¹H NMR(CDCl₃) δ 8.01-7.92(m,fluoro-phenyl)-ethanone 1H), 7.86-7.75(m, 1H), 7.57-7.50(m, 1H),7.35-7.22(m, 2H), 7.08-6.93(m, 2H), 4.47 (s, 2H). TLC (SiO₂):R_(f)0.57(30% ethyl acetate/hexanes)

Preparation 45 1-Pyridin-2-yl-2-quinolin-4-yl-ethanone

To a solution of diisopropylamine (44.9 mL, 320 mmol) in THF (500 mL) at−78° C. add 1.6 M n-butyl lithium in hexane (200 mL, 320 mmol). Stir for10 minutes and add dropwise a solution of lepidine (42.9 g, 300 mmol) inTHF (200 mL) over 20 minutes at −78° C. and quickly add a solution ofethyl picolinate (48.3 g, 320 mmol). Allow the reaction to warm slowlyto 0° C. and quench by pouring into water (1L). Add ethyl acetate (1L).Dissolve residual solids by adding Acetic acid (20 mL). Separate thelayers and extract the aqueous layer with one portion of ethyl acetate(100 mL). Combine the organic extracts, dry over sodium sulfate, andconcentrate in vacuo. Triturate the crude oil with hexane/ether to give36 g of the title compound. Concentrate the filtrate. Chromatograph theresidue on silica gel (elute with 10:9:1 CH₂Cl₂, ether, MeOH).Precipitate the purified product from ether/hexane to give 21 g of thetitle compound. Combined yield: 57 g (76%) of title compound as a yellowcrystalline solid. MS ES⁺ m/e 249.0 (M+1).

By the method of PREPARATION 45 the following compounds were prepared:Prep. # Product Name Physical data Comments 462-(6,7-Dimethoxy-quinolin-4- MS ES⁺ m/e 323.1 (M + 1).yl)-1-(6-methyl-pyridin-2-yl)- ethanone 47 2-(6-Ethoxy-quinolin-4-yl)-1-MS ES⁺ m/e 307.1 (M + 1). (6-methyl-pyridin-2-yl)- ethanone 481-Pyridin-2-yl-2-quinolin-4-yl- MS ES⁺ m/e 251 (M + 1). ethanone 492-(7-Ethoxy-quinolin-4-yl)-1- ¹H-NMR(CDCL₃): δ 8.74(d,pyridin-2-yl-ethanone 1H, J=4Hz), 7.97(d, 1H, J=8Hz), 7.84(d, 1H,J=8Hz), 7.71(t, 1H, J=8Hz), 7.42(d, 1H, J=8Hz), 7.36(s, 1H, J=4Hz),7.26(m, 1H, J=4Hz), 7.18(d, 1H, J=4Hz), 4.97(s, 2H, J=4Hz), 4.18(q, 2H,J=5Hz), 2.60(s, 3H, J=4Hz), 1.48(t, 3H, J=7Hz) 502-(7-Ethoxy-quinolin-4-yl)-1- MS ES⁺ m/e 307.1 (M + 1).(6-methyl-pyridin-2-yl)- ethanone 51 1-(6-Methyl-pyridin-2-yl)-2- MS ES⁺m/e 263.1 (M + 1). quinolin-4-yl-ethanone 52 1-(6-Ethyl-pyridin-2-yl)-2-MS ES⁺ m/e 277.33 (M + 1). quinolin-4-yl-ethanone 531-Furan-2-yl-2-quinolin-4-yl- TOF MS exact mass m/z = ethanone 238.0868.Found: 238.0888. 54 2-Quinolin-4-yl-1-thiophen-2- TOF MS exact mass m/z= yl-ethanone 254.0640. Found: 254.0657. 551-Pyridin-2-yl-2-pyridin-4-yl- MS ES⁺ m/e 199.2 (M + 1). KHMDS ethanone56 2-(6-Ethoxy-quinolin-4-yl)-1- MS ES⁺ m/e 307.1 (M + 1).(6-methyl-pyridin-2-yl)- ethanone 57 1-(6-Chloro-pyridin-2-yl)-2- ¹HNMR(CDCl₃): δ 8.81(m, quinolin-4-yl-ethanone 1H), 8.08(m, 1H), 7.96(m,2H), 7.76(m, 1H), 7.63(m, 1H), 7.41 (m, 2H), 7.34(m, 1H), 4.94(s, 2H).58 1-(6-Fluoro-pyridin-2-yl)-2- MS APCI⁺ m/e 267(M + 1).quinolin-4-yl-ethanone TLC (SiO₂): R_(f)0.30(1:2 acetone/hexanes) 591-(5-Butyl-pyridin-2-yl)-2- TLC (SiO₂): R_(f)0.40(1:1quinolin-4-yl-ethanone acetone/hexanes) 60 2-(8-Fluoro-quinolin-4-yl)-1-¹H NMR(CDCl₃) δ 8.90-8.85 KHMDS (6-methyl-pyridin-2-yl)- (m, 1H),7.90-7.70(m, 2H), ethanone 7.50-7.30(m, 3H), 5.05(s, 2H), 2.70(s, 3H).61 1-(6-Methyl-pyridin-2-yl)-2- ¹H NMR(CDCl₃) δ 8.97-8.94(6-trifluoromethyl-quinolin-4- (m, 1H), 8.55-8.51(m, 1H), yl)-ethanone8.25-8.20(m, 1H), 7.98-7.93(m, 1H), 7.89-7.83(m, 1H), 7.77- 7.69(m, 1H),7.54-7.50(m, 1H), 7.41-7.32(m, 1H), 5.00(s, 2H), 2.69(s, 3H). 622-(7-Bromo-quinolin-4-yl)-1- ¹H NMR(CDCl₃) δ 8.85(m,(6-methyl-pyridin-2-yl)- 1H), 8.30(s, 1H), 8.00-7.60(m, ethanone 4H),7.45-7.35(m, 2H), 5.05(s, 2H), 2.65(s, 3H). 632-(7-Trifluoromethyl-quinolin- ¹H NMR(CDCl₃) δ 8.88(m,4-yl)-1-(6-methyl-pyridin-2- 1H), 8.15-8.10(m, 1H), 8.00(s, yl)-ethanone1H), 7.98-7.80(m, 2H), 7.75- 7.65(m, 1H), 7.50(m, 1H), 7.35-7.33(m, 1H),5.00(s, 2H), 2.70(s, 3H) 64 2-(6-Bromo-quinolin-4-yl)-1- ¹H NMR(CDCl₃) δ8.89-8.81 (6-methyl-pyridin-2-yl)- (m, 1H), 8.40(s, 1H), 8.03-7.99ethanone (m, 1H), 7.90-7.85(m, 1H), 7.79-7.67(m, 2H), 7.49-7.38(m, 2H),4.97(s, 2H), 2.71(s, 3H) 65 1-Pyridin-2-yl-2-quinolin-4-yl- ¹HNMR(CDCl₃) δ 8.85-8.80 KHMDS ethanone (m, 1H), 8.10-8.00(m, 2H),7.85-7.87(m, 1H), 7.73-7.60(m, 2H), 7.50-7.43(m, 1H), 7.40- 7.30(m, 2H),5.00(s, 2H) 66 2-(7-Bromo-quinolin-4-yl)-1- ¹H NMR(CDCl₃) δ 8.85(m,KHMDS pyridin-2-yl-ethanone 1H), 8.30(s, 1H), 8.00-7.60 (m, 4H),7.45-7.35(m, 3H), 5.05 (s, 2H) 67 2-(7-Methoxy-quinolin-4-yl)- ¹HNMR(CDCl₃) δ 8.79-8.72 KHMDS 1-(6-methyl-pyridin-2-yl)- (m, 1H),8.01-7.96(m, 1H), ethanone 7.90-7.83(m, 1H), 7.79-7.70 (m, 1H),7.49-7.42(m, 1H), 7.40-7.37(m, 1H), 7.30-7.24(m, 1H), 7.23-7.20(m, 1H),5.05(s, 2H), 3.94(s, 3H), 2.70(s, 3H). 68 2-(7-Methoxy-quinolin-4-yl)-MS APCI⁺ m/e 279 (M + 1). KHMDS 1-pyridin-2-yl-ethanone 692-(7-Chloro-quinoline-4-yl)-1- mp 88-90° C. (6-methyl-pyridin-2-yl)- EACalcd. for C₁₇H₁₃ClN₂O: C, ethanone 68.81; H, 4.41; O, 9.44; Found: C,48.48; H, 4.38; N, 9.63 70 2-(6,7-di-Fluoro-quinoline-4- MS ES⁺ m/e 299(M + 1). yl)-1-(6-methyl-pyridin-2-yl)- ethanone 712-(6,7-di-Chloro-quinolin-4- MS ES⁻m/e 343 (M − 1).yl)-1-6-ethyl-pyridin-2-yl)- ethanone

Preparation 722-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-boronic acid

A solution of 3-bromo-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine(PREP. 17, 0.2 g, 0.69 mmol) in THF (10 mL) is cooled to −78° C. andtreated with tert-butyllithium (1.7 M in pentane, 1.6 mL, 2.8 mmol).This solution is stirred for 30 minutes at −78° C., treated withtriisopropyl borate (0.39 g, 2.08 mmol), and stirred for 2 hr at −78° C.The reaction is then quenched with 1N HCl and stirred for 30 minutes atroom temp. Evaporation leads to the solid crude product that is usedwithout further purification. MS ES⁺ m/e 253.9 (M+1).

Preparation 73 Methyl 6-chloropicolinate

Add thionyl chloride (3.7 mL, 50.8 mmol) to a solution of6-chloropicolinic acid (4.0 g, 25.4 mmol) in methanol (85 mL) at 0° C.Stir the resultant solution for 15 minutes at 0° C., 0.5 hours at roomtemperature, and 6 hours at 50° C. Concentrate the reaction in vacuo anddilute with CHCl₃ (150 mL). Wash the organic solution with saturatedaqueous sodium bicarbonate (3×100 mL), and brine (1×100 mL) and dry withsodium sulfate. Filtration and concentration afford methyl6-chloropicolinate 4.38 g (100%) as a white solid.

¹H NMR (CDCl₃): δ 8.05 (m, 1H), 7.73 (m, 1H), 7.42 (m, 1H), 3.95 (s,3H).

Preparation 74 6-Fluoro-pyridine-2-carboxylic acid

Add potassium permanganate (12.8 g, 81.0 mmol) to a solution of2-fluoro-5-methylpyridine (3.0 g, 27.0 mmol) in water (135 mL). Heat thereaction to 100° C. for 4 hours. While the reaction is hot, filterthrough Celite® Rinse the filter cake with hot water (2×50 mL) andconcentrate the combined aqueous solutions in vacuo to a volume of 50mL. Acidify with concentrated HCl and concentrate to dryness in vacuo toprovide the title compound as a white solid which is used directly inthe next step. MS APCI⁺ m/e 142 (M+1).

Preparation 75 6-Fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide

Add N-methylmorpholine (6 mL, 52 mmol) and isobutylchloroformate (3.5mL, 26.9 mmol) to a solution of 6-fluoropyridine-2-carboxylic acid (3.8g, 26.9 mmol) in methylene chloride at 0° C. After 15 minutes addO,N-dimethylhydroxylamine hydrochloride (2.6 g, 26.9 mmol) andN-methylmorpholine (3 mL, 26.9 mmol). Stir the reaction at 0° C. for 15minutes and then room temperature for 17 hours. Dilute the reaction withmethylene chloride and wash sequentially with water (1×50 mL), 10%aqueous citric acid (1×50 mL), brine (1×50 mL), saturated aqueous sodiumbicarbonate (1×50 mL), and brine (1×50 mL). Dry the resulting organicsolution with Na₂SO₄, filter, and purify by flash column chromatography(Silica Gel, 20% acetone/hexanes) to provide the title compound 0.97 g(18% from 2-fluoro-5-methylpyridine) as a clear, yellow oil.

MS APCI⁺ m/e 185 (M+1).

TLC (SiO₂): Rf 0.40 (1:3 acetone/hexanes).

Preparation 76 5-Butyl-pyridine-2-carboxylic acid methoxy-methyl-amide

Add N-methylmorpholine (1.22 mL, 11.1 mmol) and isobutylchloroformate(1.44 mL, 11.1 mmol) to a solution of fusaric acid (2.0 g, 11.1 mmol) inmethylene chloride at 0° C. After 15 minutes addO,N-dimethylhydroxylamine hydrochloride (1.1 g, 11.1 mmol) andN-methylmorpholine (1.22 mL, 11.1 mmol). Stir the reaction for at 0° C.15 minutes and then room temperature for 19 hours. Dilute the reactionwith methylene chloride and wash with water (1×50 mL), 10% aqueouscitric acid (1×50 mL), brine (1×50 mL), saturated aqueous sodiumbicarbonate (1×50 mL), and brine (1×50 mL). Dry the organic solutionwith sodium sulfate, filter, and concentrate in vacuo to provide thetitle compound 3.2 g (100%) as a clear yellow oil.

MS APCI⁺ m/e 201 (M+1). TLC (SiO₂): R_(f) 0.70 (1:1 ethylacetate/methylene chloride).

Preparation 77 8-Fluoro-4-methyl-quinoline

Add H₂SO₄ (14.4 mL, 270 mmol) to a solution of 2-fluoroaniline (20.0 g,180 mmol) in 1,4-dioxane (1L) at room temperature. Heat the mixture toreflux and add methyl vinyl ketone (19.5 mL, 270 mmol) in 1,4-dioxane(50 mL) dropwise over 3 hours. Continue to heat for 1 hour after theaddition, then remove the solvent under vacuum. Dissolve the residue inwater (100 mL), neutralize with Na₂CO₃ and extract with CH₂Cl₂. Wash thecombined organic extracts with water and brine, dry with anhydrousNa₂SO₄ and filter the mixture. Concentrate the filtrate; chromatographthe residue with silica gel (elute with 20% EtOAc in hexanes) to givethe title compound 12 g (41%) as a yellowish solid.

¹(CDCl₃) δ 8.80-8.75 (m, 1H), 7.85-7.80 (m, 3H), 7.60-7.30 (m, 3H), 3.70(s, 3H).

By the method of PREPARATION 77 the following compounds were prepared:PREP. Product # (Chemical Name) Physical Data 78 6-Bromo-4-methyl- ¹HNMR(CDCl₃) δ 8.78-8.75(m, 1H), 8.16-8.11 quinoline (m, 1H), 7.99-7.91(m,1H), 7.81-7.72(m, 1H), 7.28-7.19 9m, 1H), 2.67(s, 3H). 797-Trifluoromethyl-4- ¹H NMR(CDCl₃) δ 8.80-8.75(m, 1H), 8.15-8.10methyl-quinoline (m, 1H), 7.80(s, 1H), 7.60-7.55(m, 1H), 7.30-7.27 (m,1H), 2.70(s, 3H). 80 7-Bromo-4-methyl- ¹H NMR(CDCl₃) δ 8.80-8.75(m, 1H),8.30 quinoline (s, 1H), 7.90-7.85(m, 1H), 7.70-7.65(m, 1H), 7.25-7.20(m, 1H), 2.65(s, 3H). 81 4-Methyl-6- ¹H NMR(CDCl₃) δ 8.91-8.86(m,1H), 8.32(s, 1H), trifluoromethyl- 8.27-8.19(m, 1H), 7.91-7.86(m, 1H),7.39-7.32(m, quinoline 1H), 2.69(s, 3H). 82 7-Methoxy-4-methyl- ¹HNMR(CDCl₃) δ 8.71-8.66(m, 1H), 7.91-7.87 quinoline (m, 1H), 7.44-7.40(m,1H), 7.28-7.18(m, 1H), 7.11-7.06(m, 1H), 3.95(s, 3H), 2.67(s, 3H). 837-Chloro-4-methyl- quinoline 84 7-Ethoxy-4-methyl- TOF MS ES⁺ exact masscalculated for C₁₂H₁₄NO quinoline (p + 1): m/z = 188.1075 Found:188.1059 85 6,7-di-Methoxy-4- TOF MS ES⁺ exact mass calculated forC₁₂H₁₄NO₂ methyl-quinoline (p + 1): m/z = 204.1025 Found: 204.1010 866,7-di-Chloro-4- MS ES⁺ m/e 212 (M + 1) methyl-quinoline 876,7-di-Fluoro-4- MS ES⁺ m/e 212 (M + 1) methyl-quinoline 886-Ethoxy-4-methyl- TOF MS ES⁺ exact mass calculated for C₁₂H₁₄NOquinoline (p + 1): m/z = 188.1075. Found: 188.1079

Preparation 89 5-Bromo-benzofuran-2-carboxylic acid ethyl ester

A solution of 5-bromo-salicylaldehyde (5.0 g, 25 mmol) and bromodiethylmalonate (8.9 g, 37 mmol) in methyl ethyl ketone (50 mL) istreated with potassium carbonate (6.8 g, 50 mmol) and heated to reflux.The reaction is stirred over 3 days at reflux. The reaction is thenconcentrated to a crude solid that is purified by silica gel columnchromatography (9:1 hexane/EtOAc) to afford 5.2 g (78%) of the desiredproduct. ¹H NMR (CDCl₃) 7.81 (d, 1H), 7.26-7.55 (m, 3H), 4.44 (q, 2H),1.42 (t, 3H).

Preparation 904-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-ol

To a solution of7-methoxy-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline(1.3 g, 3.57 mmol) in DMF (36 mL), add ethanethiol (5.3 mL, 71.4 mmol),followed by sodium hydride (60% dispersion in mineral oil, 2.9 g, 71.4mmol). After all of the gas has evolved, the mixture is heated at 80° C.for 4 hours, then cooled to room temperature. Saturated aqueous NH₄Cl (5mL) is added, and the mixture concentrated. The residue is dissolved inmethylene chloride, washed with water and concentrated to give the titlecompound 1.16 g (93%) as a yellow solid.

¹H NMR (CD₃OD) δ 8.73-8.68 (m, 1H), 8.60-8.56 (m, 1H), 7.56-7.49 (m,1H), 7.41-7.18 (m, 5H), 7.15-7.01 (m, 3H), 6.89-6.82 (m, 1H), 2.32 (s,3H).

Preparation 914-(2-Pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)quinolin-7-ol

Add ethanethiol (6.8 mL, 92.5 mmol), followed by a sodium hydride (60%dispersion in mineral oil, 3.7 g, 92.5 mmol) to a solution of7-methoxy-4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline (1.63g, 4.6 mmol) in DMF (50 mL) at room temperature. Following the sameprocedure described above affords the title compound 0.8 g (52%) as ayellow solid.

Preparation 927-(3-Chloro-propoxy)-4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline

4-(2-Pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-ol in asolution of DMF and MeOH is treated with 1-bromo-3-chloropropane (3equiv) and cesium carbonate (2 equiv). The reaction is heated to 60° C.and stirred overnight. The reaction is then purified on silica gelcolumn (see Prep. 77) chromatography to afford the desired product. MSES⁺ m/e 415.0 (M+1).

Preparation 937-(2-Chloro-ethoxy)-4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline

4-(2-Pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-ol in asolution of DMF and MeOH was treated with 1-bromo-2-chloroethane (3equiv) and cesium carbonate (2 equiv). The reaction was heated to 60° C.and stirred overnight. As described above, the desired product was thenobtained upon chromatographic purification (EtOAc, followed by MeOH,then 2 M NH₃ in MeOH). Yield; 30% overall from Prep. 90. MS ES⁺ m/e401.0 (M+1).

EXAMPLE 13-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine

A solution of3-bromo-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine(0.25 g, 0.9mmol) and p-fluorophenyl-boronic acid (0.15 g, 1.04 mmol), in DME (10mL) is purged with argon. The solution is treated with NaOH (0.07 g, 1.7mmol) and (PPh₃)₄Pd (0.05 g, 0.04 mmol) then heated at reflux overnight.The reaction is then cooled, diluted in EtOAc, and washed with water andbrine. The organic solution is dried over MgSO₄ and the solvent removedin vacuo. The residue is purified by silica gel column chromatographyusing a mixture of hexanes/EtOAc to afford 0.164 g (62%) of desiredproduct as a white solid. UV (95% EtOH) λ_(max) 248 nm (ε 20386). TOF MSES⁺ exact mass calculated for C₁₉H₁₄FN₃ (p+1): m/z=304.1250. Found:304.1249. Anal. Calcd for C₁₉H₁₄FN₃: C, 75.23; H, 4.65; N, 13.85. Found:C, 75.10; H, 4.76; N, 13.70.

By the method of EXAMPLE 1 the following compounds were prepared:Product Starting Physical EX # (Chemical Name) Material A StartingMaterial B Data Comments 2 Dimethyl-{4-[2-(6- 3-Bromo-2-(6- 4-(N,N- TOFMS methyl-pyridin-2- methyl- Dimethylamino)Phenyl ES⁺exactyl)-pyrazolo[1,5- pyridin-2-yl)- boronic acid mass a]pyridin-3-yl]-pyrazolo[1,5- calculated phenyl}-amine a]pyridine for (Prep. 17)C₂₁H₁₂₀N₄ (p + 1): m/z = 329.1766. Found: 329.1768. 3 3-(4-Methoxy-3-Bromo-2-(6- p- Anal. phenyl)-2-(6- methyl- methoxyphenylboronic Calcdfor methyl-pyridin-2- pyridin-2-yl)- acid C₂₀H₁₇N₃ yl)-pyrazolo[1,5-pyrazolo[1,5- O: C, a]pyridine a]pyridine 76.17; H, (Prep. 17) 5.43; N,13.32. Found: C, 75.84; H, 5.42; N, 13.07. 4 3-(4- 3-Bromo-2-(6- 4- TOFMS Methanesulfonyl- methyl-pyridin- (Methanesulfonyl)ben- ES⁺exactphenyl)-2-(6- 2-yl)- zeneboronic acid mass methyl-pyridin-2-pyrazolo[1,5- calculated yl)-pyrazolo[1,5- a]pyridine (Prep. fora]pyridine 17) C₂₀H₁₈N₃O₂S (p + 1): m/z = 364.1120. Found: 364.1134 52-(6-Methyl- 3-Bromo-2-(6- Phenylboronic acid Anal. Use 5:1pyridin-2-yl)-3- methyl-pyridin- Calcd for Toluene: phenyl- 2-yl)-C₁₉H₁₅N₃: MeOH pyrazolo[1,5- pyrazolo[1,5- C, 79.98; instead ofa]pyridine a]pyridine (Prep. H, 5.30; DME as 17) N, 14.73. solvent.Found: C, Use 79.94; H, Na2CO3 5.40; N, instead of 14.59. NaOH. 62-(6-Methyl- 3-Bromo-2-(6- Pyridine-4-boronic acid MS ES⁺ Use 5:1pyridin-2-yl)-3- methyl-pyridin- m/e 287.2 Toluene: pyridin-4-yl- 2-yl)-(M + 1). MeOH pyrazolo[1,5- pyrazolo[1,5- instead of a]pyridinea]pyridine (Prep. DME as 17) solvent. Use Na2CO3 instead of NaOH. 73-(4-Fluoro- 3-Bromo-2-(6- p-Fluorophenylboronic MS ES⁺ Use 5:1phenyl)-2-(6- methyl- acid m/e 380.2 Toluene: methyl-pyridin-2-pyridin-2-yl)- (M + 1). MeOH yl)-6-phenyl- 6-phenyl- instead ofpyrazolo[1,5- pyrazolo[1,5- DME as a]pyridine a]pyridine solvent. (Prep.18) Use Na2CO3 instead of NaOH. 8 3-(4-Fluoro- 3-Bromo-6-p-Fluorophenylboronic MS ES⁺ Use 5:1 phenyl)-6- methanesulfon- acid m/e382.1 Toluene: methanesulfonyl-2- yl-2-(6-methyl- (M + 1). MeOH(6-methyl-pyridin- pyridin-2-yl)- instead of 2-yl)-pyrazolo[1,5-pyrazolo[1,5- DME as a]pyridine a]pyridine solvent. (Prep. 20) UseNa2CO3 instead of NaOH. 9 2-(6-Methyl- 3-Bromo-2-(6- 4- MS ES⁺ Use 5:1pyridin-2-yl)-3-(4- methyl- Trifluoromethylphenyl- m/e 354.0 Toluene:trifluoromethyl- pyridin-2-yl)- boronic acid (M + 1). MeOH phenyl)-pyrazolo[1,5- instead of pyrazolo[1,5- a]pyridine DME as a]pyridine(Prep. 17) solvent. Use Na2CO3 instead of NaOH. 10 3-(6-Methoxy-3-Bromo-2-(6- 2-Methoxy-5- TOF MS Use 5:1 pyridin-3-yl)-2-(6- methyl-Pyridineboronic acid ES⁺exact Toluene: methyl-pyridin-2- pyridin-2-yl)-mass MeOH yl)-pyrazolo[1,5- pyrazolo[1,5- calculated instead ofa]pyridine a]pyridine for DME as (Prep. 17) C₁₉H₁₆N₄O solvent. (p + 1):Use m/z = Na2CO3 317.1402. instead of Found: NaOH. 317.1416. 113-Benzo[1,3]dioxol- 3-Bromo-2-(6- 3,4- TOF MS Use 5:1 yl-2-(6-methyl-methyl- Methylenedioxybenzene- ES⁺exact Toluene: pyridin-2-yl)-pyridin-2-yl)- boronic acid mass MeOH pyrazolo[1,5- pyrazolo[1,5-calculated instead of a]pyridine a]pyridine for DME as (Prep. 17)C₂₀H₁₅N₃O₂ solvent. (p + 1): Use m/z = Na2CO3 330.1243. instead ofFound: NaOH. 330.1243. 12 3-(3,5-Difluoro- 3-Bromo-2-(6- 3,5- TOF MS Use5:1 phenyl)-2-(6-methy methyl- Difluorophenylboronic ES⁺exact Toluene:pyridin-2-yl)- pyridin-2-yl)- acid mass MeOH pyrazolo[1,5- pyrazolo[1,5-calculated instead of a]pyridine a]pyridine for DME as (Prep. 17)C₁₉H₁₃F₂N₃ solvent. (p + 1): Use m/z = Na2CO3 322.1156. instead ofFound: NaOH. 322.1147. 13 2-(6-Methyl-pyridi 3-Bromo-2-(6- p-Tolylbornicacid TOF MS Use 5:1 2-yl)-3-p-tolyl- methyl- ES⁺exact Toluene:pyrazolo[1,5- pyridin-2-yl)- mass MeOH a]pyridine pyrazolo[1,5-calculated instead of a]pyridine for DME as (Prep. 17) C₂₀H₁₇N₃ solvent.(p + 1): m/z = Use 300.1501. Na2CO3 Found: instead of 300.1522 NaOH. 143-(1H-Indol-5-yl- 3-Bromo-2-(6- 5-Indolylboronic acid TOF MS Use 5:12-(6-methyl- methyl- ES⁺exact Toluene: pyridin-2-yl)- pyridin-2-yl)-mass MeOH pyrazolo[1,5- pyrazolo[1,5- calculated instead of a]pyridinea]pyridine for DME as (Prep. 17) C₂₁H₁₆N₄ solvent. (p + 1): m/z = Use325.1453. Na2CO3 Found: instead of 325.1465 NaOH. 15 3-[2-(6-Methyl-3-Bromo-2-(6- Benzamide-3-boronic MS ES⁺ Use 5:1 pyridin-2-yl)- methyl-acid m/e 329.1 Toluene: pyrazolo[1,5- pyridin-2-yl)- (M + 1). MeOHa]pyridin-3-yl]- pyrazolo[1,5- instead of benzamide a]pyridine DME as(Prep. 17) solvent. Use Na2CO3 instead of NaOH. 16 3-(3,4-Dimethoxy-3-Bromo-2-(6- 3,4- MS ES⁺ Use 5:1 phenyl)-2-(6- methyl-Dimethoxyphenylboron- m/e 346.2 Toluene: methyl-pyridin-2-pyridin-2-yl)- ic acid (M + 1). MeOH yl)-pyrazolo[1,5- pyrazolo[1,5-instead of a]pyridine a]pyridine DME as (Prep. 17) solvent. Use Na2CO3instead of NaOH. 17 N,N-Dimethyl-3-[2- PREP. 17 N,N- MS ES⁺ m/e Use 5:1(6-methyl-pyridin- Dimethylbenzamide-3- 357.2 Toluene:2-yl)-pyrazolo[1,5- boronic acid (M + 1). MeOH a]pyridin-3-yl]- insteadof benzamide DME as solvent. Use Na2CO3 instead of NaOH. 182-Fluoro-5-[2-(6- PREP. 17 4-Fluoro-3- TOF MS Use 5:1 methyl-pyridin-2-formylbenzene boronic ES⁺exact Toluene: yl)-pyrazolo[1,5- acid mass MeOHa]pyridin-3-yl]- calculated instead of benzaldehyde for DME as C₁₂H₁₄NOsolvent. (p + 1): m/z = Use 332.1199. Na2CO3 Found: instead of 332.1211NaOH. 19 4-[2-(6-Methyl- 3-Bromo-2-(6- 4-(4,4,5,5-Tetramethyl- MS ES⁺m/e Use 5:1 pyridin-2-yl)- methyl- 1,3,2-dioxaborolan-2- 301.1 Toluene:pyrazolo[1,5- pyridin-2-yl)- yl) aniline (M + 1). MeOH a]pyridin-3-yl]-pyrazolo[1,5- instead of phenylamine a]pyridine DME as (Prep. 17)solvent. Use Na2CO3 instead of NaOH. 20 N-{4-[2-(6-Methyl- 3-Bromo-2-(6-4-(4,4,5,5- MS ES⁺ Use 5:1 pyridin-2-yl)- methyl- Tetramethyl-1,3,2- m/e343.1 Toluene: pyrazolo[1,5- pyridin-2-yl)- dioxaborolan-2-yl) (M + 1).MeOH a]pyridin-3-yl]- pyrazolo[1,5- acetamide instead ofphenyl}-acetamide a]pyridine DME as (Prep. 17) solvent. Use Na2CO3instead of NaOH. 21 4-[2-(6-Methyl- 3-Bromo-2-(6- 4-(4,4,5,5- MS ES⁺ Use5:1 pyridin-2-yl)- methyl- Tetramethyl-1,3,2- m/e 302.0 Toluene:pyrazolo[1,5- pyridin-2-yl)- dioxaborolan-2-yl) (M + 1). MeOHa]pyridin-3-yl]- pyrazolo[1,5- phenol instead of phenol a]pyridine DMEas (Prep. 17) solvent. Use Na2CO3 instead of NaOH. 22 3-(2,3-Dihydro-3-Bromo-2-(6- 1,4-Benzodioxane-6- TOF MS Use 5:1 benzo[1,4]dioxin-6-methyl- boronic acid ES⁺exact Toluene: yl)-2-(6-methyl- pyridin-2-yl)-mass MeOH pyridin-2-yl)- pyrazolo[1,5- calculated instead ofpyrazolo[1,5- a]pyridine for DME as a]pyridine (Prep. 17) C₂₁H₁₈N₃O₂solvent. (p + 1): m/z = Use 344.1399. Na2CO3 Found: instead of 344.1412.NaOH. 23 3-(3-Methoxy- 3-Bromo-2-(6- 3-Methoxyphenyl MS ES⁺phenyl)-2-(6- methyl- boronic acid m/e 316.0 methyl-pyridin-2-pyridin-2-yl)- (M + 1). yl)-pyrazolo[1,5- pyrazolo[1,5- a]pyridinea]pyridine (Prep. 17) 24 3-(3-Fluoro- 3-Bromo-2-(6-3-Fluorophenylboronic MS ES⁺ phenyl)-2-(6- methyl- acid m/e 304.0methyl-pyridin-2- pyridin-2-yl)- (M + 1). yl)-pyrazolo[1,5-pyrazolo[1,5- a]pyridine a]pyridine (Prep. 17) 25 2-(6-Ethyl-pyridin-3-Bromo-2-(6- 4- TOF MS 2-yl)-3-(4- ethyl-pyridin- MethoxyphenylboronicES⁺exact methoxy-phenyl)- 2-yl)- acid mass pyrazolo[1,5- pyrazolo[1,5-calculated a]pyridine a]pyridine for (Prep. 22) C₂₁H₁₉N₃O (p + 1): m/z =330.1606. Found: 330.1602 26 4-[2-(6-Ethyl- (6-ethyl-4-(4,4,5,5-Tetramethyl- TOF MS pyridin-2-yl)- pyridin-2-yl)-1,3,2-dioxaborolan-2- ES⁺exact pyrazolo[1,5- pyrazolo[1,5- yl) phenolmass a]pyridin-3-yl]- a]pyridine calculated phenol (Prep. 22) forC₂₀H₁₇N₃O (p + 1): m/z = 316.1450. Found: 316.1435.

EXAMPLE 27N′-{2-Fluoro-5-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-benzyl}-N,N-dimethyl-ethane-1,2-diamine

A solution of2-fluoro-5-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-benzaldehyde(0.05 g, 0.15 mmol), N,N-dimethyl-ethylenediamine (0.013 g, 0.15 mmol),trimethyl orthoformate (2 mL) in MeOH (5 mL) is stirred for 2 hours atroom temperature. The reaction is then treated with sodium borohydride(6.8 mg, 0.18 mmol) and stirred overnight. The reaction is then quenchedwith 2N NaOH and stirred for 30 minutes. The solution is diluted inCH₂Cl₂ and washed with saturated aqueous NaHCO₃, brine, and dried oversodium sulfate. The solvent is removed in vacuo to afford 0.06 g (100%)of desired product. MS ES⁺ m/e 404.1 (M+1).

EXAMPLES 284-[2-(6-Chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline

Add 1-aminopyridinium iodide (780 mg, 3.53 mmol),N,N-diisopropylethylamine (0.62 mL, 3.53 mmol),1-(6-chloro-pyridin-2-yl)-2-quinolin-4-yl-ethanone (500 mg, 1.77 mmol),and ethanol (8 mL) to a sealed tube apparatus. The sealed vessel isheated at 110° C. for 5 hours. After cooling, the crude is concentratedin vacuo. Purification by flash column chromatography (Silica Gel,25-40% acetone/hexanes) provides the title compound 119 mg (19%) as anorange solid.

MS APCI⁺ m/e 357 (M+1).

By the method of EXAMPLE 28 the following compounds were prepared: EX. #Product Name Physical Data Pyridinium Salt 29 3-(4-Fluoro-phenyl)-2- MSES⁺ m/e 290 (M + 1). 1-Amino-pyridinium; iodidepyridin-2-yl-pyrazolo[1,5- a]pyridine 30 7-Ethoxy-4-(4-phenyl-2- MS ES⁺m/e 443 (M + 1). 1-Amino-3-phenyl- pyridin-2-yl-pyrazolo[1,5-pyridinium; 2,4,6- a]pyridin-3-yl)-quinoline trimethyl- benzenesulfonate31 7-Ethoxy-4-(2-pyridin-2-yl- MS ES⁺ m/e 367 (M + 1).1-Amino-pyridinium; iodide pyrazolo[1,5-a]pyridin-3- yl)-quinoline 324-[2-(6-Methyl-pyridin-2- TOF MS ES⁺ exact 1-Amino-pyridinium; iodideyl)-pyrazolo[1,5-a]pyridin- mass calculated for 3-yl]-quinoline C₂₂H₁₇N₄(p + 1): m/z = 337.1453. Found: 337. 33 7-Ethoxy-4-[2-(6-methyl- TOF MSES⁺ exact 1-Amino-pyridinium; iodide pyridin-2-yl)-pyrazolo[1,5- masscalculated for a]pyridin-3-yl]-quinoline C₂₄H₂₁N₄O (p + 1): m/z =381.1715. Found: 381.1722 34 4-[2-(6-Ethyl-pyridin-2-yl)- TOF MS ES⁺exact 1-Amino-pyridinium; iodide pyrazolo[1,5-a]pyridin-3- masscalculated for yl]-quinoline C₂₃H₁₉N₄ (p + 1): m/z = 351.1610. Found:351.1628 35 6,7-Dimethoxy-4-[2-(6- TOF MS ES⁺ exact 1-Amino-pyridinium;iodide methyl-pyridin-2-yl)- mass calculated forpyrazolo[1,5-a]pyridin-3- C₂₄H₂₁N₄O2 (p + 1): yl]-quinoline m/z =397.1665. Found: 397.1665 36 7-Chloro-4-[2-(6-methyl- MS ES⁺ m/e 371(M + 1). 1-Amino-pyridinium; iodide pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline 37 6-Ethoxy-4-[2-(6-methyl- MS ES⁺ m/e 381(M + 1). 1-Amino-pyridinium; iodide pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline 38 3-(4-Fluoro-naphthalen-1- MS ES⁺ m/e 354(M + 1). 1-Amino-pyridinium; iodide yl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine 39 4-(2-Furan-2-yl- TOF MS ES⁺ exact1-Amino-pyridinium; iodide pyrazolo[1,5-a]pyridin-3- mass calculated foryl)-quinoline C₂₀H₁₄N₃O (p + 1): m/z = 312.1137. Found: 312.1126 404-(2-Thiophen-2-yl- TOF MS ES⁺ exact 1-Amino-pyridinium; iodidepyrazolo[1,5-a]pyridin-3- mass calculated for yl)-quinoline C20H14N3SC₂₀H₁₄N₃S (p + 1): m/z = 328.0908. Found: 328.0914 417-Methoxy-4-[2-(6-methyl- MS ES⁺ m/e 367 (M + 1). 1-Amino-pyridinium;iodide pyridin-2-yl)-pyrazolo[1,5- a]pyridin-3-yl]-quinoline 426,7-Difluoro-4-[2-(6-methyl- MS ES⁺ m/e 373 (M + 1). 1-Amino-pyridinium;iodide pyridin-2-yl)-pyrazolo[1,5- a]pyridin-3-yl]-quinoline 436,7-Dichloro-4-[2-(6-ethyl- MS ES⁺ m/e 419 (M + 1). 1-Amino-pyridinium;iodide pyridin-2-yl)-pyrazolo[1,5- a]pyridin-3-yl]-quinoline 444-[2-(6-Ethyl-pyridin-2-yl)- TOF MS ES⁺ exact 1-Amino-pyridinium; iodidepyrazolo[1,5-a]pyridin-3- mass calculated foryl]-6,7-dimethoxy-quinoline C₂₅H₂₃N₄O2 (p + 1): m/z = 411.1821. Found:411.1828 45 6,7-Dichloro-4-[2-(6- MS ES⁺ m/e 405.0 (M + 1).1-Amino-pyridinium; iodide methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3- yl]-quinoline 46 7-Ethoxy-4-[2-(6-ethyl- TOFMS ES⁺ exact 1-Amino-pyridinium; iodide pyridin-2-yl)-pyrazolo[1,5- masscalculated for a]pyridin-3-yl]-quinoline C₂₅H₂₃N₄O (p + 1): m/z =395.1872. Found: 394.1794 47 2-(6-Ethyl-pyridin-2-yl)-3- TOF MS ES⁺exact 1-Amino-pyridinium; iodide (4-fluoro-naphthalen-1-yl)- masscalculated for pyrazolo[1,5-a]pyridine C₂₄H₁₉FN₃ (p + 1): m/z =368.1563. Found: 368.1569 48 3-(4-Fluoro-phenyl)-2-(6- TOF MS ES⁺ exact1-Amino-3- methyl-pyridin-2-yl)- mass calculated for methoxycarbonyl-pyrazolo[1,5-a]pyridine-6- C₂₂H₁₉FN₃O₂ (p + 1): pyridinium; 2,4,6-carboxylic acid ethyl ester m/z = 376.1461. trimethyl- Found: 376.1457benzenesulfonate 49 3-(4-Fluoro-phenyl)-2-(6- TOF MS ES⁺ exact1-Amino-3- methyl-pyridin-2-yl)- mass calculated for methoxycarbonyl-pyrazolo[1,5-a]pyridine-4- C₂₂H₁₉FN₃O₂ (p + 1): pyridinium; 2,4,6-carboxylic acid ethyl ester m/z = 376.1461. trimethyl- Found: 376.1464benzenesulfonate 50 3-(4-Fluoro-phenyl)-4-iodo- TOF MS ES⁺ exact1-Amino-3-iodo- 2-(6-methyl-pyridin-2-yl)- mass calculated forpyridinium; 2,4,6- pyrazolo[1,5-a]pyridine C19H14FIN3 trimethyl-C₁₉H₁₄FIN₃ (p + 1): m/z = benzenesulfonate 430.0216. Found: 430.0241 513-(4-Fluoro-phenyl)-2-(6- TOF MS ES⁺ exact 1-Amino-pyridinium; iodidepropyl-pyridin-2-yl)- mass calculated for pyrazolo[1,5-a]pyridineC21H19FN3 C₂₁H₁₉FN₃ (p + 1): m/z = 332.1563. Found: 332.1563 522-(6-Ethyl-pyridin-2-yl)-3- TOF MS ES⁺ exact 1-Amino-pyridinium; iodide(4-fluoro-phenyl)- mass calculated for pyrazolo[1,5-a]pyridine C₂₀H₁₇FN₃(p + 1): m/z = 318.1406. Found: 318.1404 53 3-Pyridin-4-yl-2-pyridin-2-MS ES⁺ m/e 273.3 (M + 1). 1-Amino-pyridinium; iodideyl-pyrazolo[1,5-a]pyridine 54 4-(2-Pyridin-2-yl- MS ES⁺ m/e 323 (M + 1).1-aminopyridinium iodide pyrazolo[1,5-a]pyridin-3-yl)- quinoline 554-[2-(6-Fluoro-pyridin-2-yl)- MS APCI⁺ m/e 340 (M + 1).1-aminopyridinium iodide pyrazolo[1,5-a]pyridin-3- yl]-quinoline 564-[2-(5-Butyl-pyridin-2-yl)- MS APCI⁺ m/e 379 (M + 1). 1-aminopyridiniumiodide pyrazolo[1,5-a]pyridin-3- yl]-quinoline 578-Fluoro-4-[2-(6-methyl- MS APCI⁺ m/e 355 (M + 1). 1-aminopyridiniumiodide pyridin-2-yl)-pyrazolo[1,5- a]pyridin-3-yl]-quinoline 584-[2-(6-Methyl-pyridin-2- MS APCI⁺ m/e 405 (M + 1). 1-aminopyridiniumiodide yl)-pyrazolo[1,5-a]pyridin- 3-yl]-6-trifluoromethyl- quinoline 597-Bromo-4-[2-(6-methyl- MS APCI⁺ m/e 415, 417 (M + 1). 1-aminopyridiniumiodide pyridm-2-yl)-pyrazolo[1,5- a]pyridin-3-yl]-quinoline 604-[2-(6-Methyl-pyridin-2- MS APCI⁺ m/e 405 (M + 1). 1-aminopyridiniumiodide yl)-pyrazolo[1,5-a]pyridin- 3-yl]-7-trifluoromethyl- quinoline 613-(3-Chloro-4-fluoro- MS APCI⁺ m/e 338 (M + 1). 1-aminopyridinium iodidephenyl)-2-(6-methyl- pyridin-2-yl)-pyrazolo[1,5- a]pyridine 622-(6-Methyl-pyridin-2-yl)- MS APCI⁺ m/e 340 (M + 1). 1-aminopyridiniumiodide 3-(2,4,5-trifluoro-phenyl)- pyrazolo[1,5-a]pyridine 633-(4-Fluoro-3- MS APCI⁺ m/e 372 (M + 1). 1-aminopyridinium iodidetrifluoromethyl-phenyl)-2-(6- methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine 64 2-(6-Chloro-pyridin-2-yl)-3- MS APCI⁺ m/e 324(M + 1). 1-aminopyridinium iodide (4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine 65 4-[2-(5-Bromo-pyridin-2- MS APCI⁺ m/e 401 (M + 1).1-aminopyridinium iodide yl)-pyrazolo[1,5-a]pyridin- 3-yl]-quinoline 664-(5-Benzyl-2-pyridin-2-yl- MS APCI⁺ m/e 413 (M + 1).4-Benzyl-pyridin-1-yl- pyrazolo[1,5-a]pyridin-3- ammonium 2,4,6-yl)-quinoline trimethyl- benzenesulfonate 67 4-[5-Benzyl-2-(6-methyl- MSAPCI⁺ m/e 505 (M + 1). 4-Benzyl-pyridin-1-yl-pyridin-2-yl)-pyrazolo[1,5- ammonium 2,4,6- a]pyridin-3-yl]-7-bromo-trimethyl- quinoline benzenesulfonate 68 4-(5-Benzyl-2-pyridin-2-yl- MSAPCI⁺ m/e 491 (M + 1). 4-Benzyl-pyridin-1-yl- pyrazolo[1,5-a]pyridin-3-ammonium 2,4,6- yl)-7-bromo-quinoline trimethyl- benzenesulfonate 692-Pyridin-2-yl-3-quinolin-4- MS APCI⁺ m/e 395 (M + 1).4-Methoxycarbonyl- yl-pyrazolo[1,5-a]pyridine- pyridin-1-yl-ammonium5-carboxylic acid ethyl ester 2,4,6-trimethyl- benzenesulfonate 702-(Pyridin-2-yl)-3-(quinolin- MS APCI⁺ m/e 395 (M + 1).3-Ethoxycarbonyl- 4-yl)-pyrazolo[1,5- pyridin-1-yl-ammoniuma]pyridine-6-carboxylic acid 2,4,6-trimethyl- ethyl esterbenzenesulfonate 71 7-Methoxy-4-[2-(6-methyl- ¹H NMR(CDCl₃) δ1-aminopyridinium iodide pyridin-2-yl)-pyrazolo[1,5- 8.87-8.84(m, 1H),8.69- a]pyridin-3-yl]-quinoline 8.63(m, 1H), 7.58-7.53 (m, 1H),7.51-7.48(m, 1H), 7.37-7.06(m, 5H), 7.02-6.95(m, 2H), 6.92- 6.85(m, 1H),3.50(s, 3H), 2.44(s, 3H). 72 7-Methoxy-4-(2-pyridin- MS APCI⁺ m/e 353(M + 1). 1-aminopyridinium iodide 2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline

EXAMPLE 734-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid methyl ester

Combine7-bromo-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline(0.18g, 0.43 mmol), triphenylphosphine (36 mg, 0.14 mmol), sodiumacetate(0.05 g, 0.61 mmol), methanol (2.7 mL), and DMF (2.7 mL). Bubblenitrogen gas through the solution for 10 minutes. Add palladium acetate(0.03 g, 0.13 mmol). Bubble nitrogen gas through the solution foranother 10 minutes. Connect a carbon monoxide balloon to the reactionvessel and heat at 80° C. for 24 hours. Evaporate the solvent in vacuo.Chromatograph the residue on silica gel (elute with 50% ethylacetate/hexanes then 75% ethyl acetate/hexanes) to afford the titlecompound 72 mg (42%) as a yellowish solid.

MS APCI⁺ m/e 395 (M+1).

EXAMPLE 744-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-6-carboxylicacid methyl ester

Using a method similar to EXAMPLE 73, using6-bromo-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline(0.14 g, 0.35 mmol) affords the title compound 0.11 g (82%) as ayellowish solid.

MS APCI⁺ m/e 395 (M+1).

EXAMPLE 754-(5-Benzyl-2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline-7-carboxylicacid methyl ester

To a solution of4-(5-benzyl-2-pyridin-2-yl-pyrazolo-[1,5-a]-pyridin-3-yl)-7-bromo-quinoline(118 mg, 0.24 mmol) in DMF (4 mL) and methanol (4 mL), addtriphenylphosphine (20 mg, 0.07 mmol) and sodium acetate (28 mg, 0.36mmol). Bubble nitrogen for 10 minutes. Add palladium acetate (16 mg,0.07 mmol) and bubble nitrogen for another 10 minutes. Bubble carbonmonoxide through the solution for 5 minutes and attach a carbon monoxideballoon. Heat the reaction mixture at 80° C. for 2 days. Cool thereaction mixture to room temperature. Add water (20 mL) and extract theaqueous solution with ethyl acetate (3×20 mL). Dry the combined organiclayers with sodium sulfate and concentrate. Purify by flash columnchromatography (SiO₂, 20-50% ethyl acetate/hexanes) to give the titlecompound 84 mg (75%) as a yellow solid.

MS APCI⁺ m/e 471 (M+1).

TLC (SiO₂): R_(f) 0.25 (30% ethyl acetate/hexanes)

EXAMPLE 763-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-6-carboxylicacid (2-dimethylamino-ethyl)-amide

Heat3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-6-carboxylicacid ethyl ester (75 mg, 0.2 mmol) in 2 ml ofN,N-dimethylethylenediamine at 90° C. for 6 hr in a sealed glass tubewith stirring. Extract reaction solution once with water/methylenechloride and concentrate the organic layer in vacuo. Purify usingpreparative TLC (Silica Gel, 90:10 methylene chloride/methanol) to give12 mg (10%) of the title compound MS ES⁺ m/e 418.2 (M+1).

By the method of EXAMPLE 76 the following compounds were prepared: EX. #Product Name Physical Data 774-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3- MS APCI⁺ m/e 451(M + 1). yl]-quinoline-6-carboxylic acid(2-dimethylamino- ethyl)-amide78 4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3- MS APCI⁺ m/e451 (M + 1). yl]-quinoline-7-carboxylic acid(2-dimethylamino-ethyl)-amide 79 5-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-TOF MS ES⁺ exact mass yl]-benzofuran-2-carboxylic acid(2-dimethylcalculated for C₂₆H₂₆N₅O₂ amino-ethyl)-amide (p + 1):m/z = 440.2086.Found: 440.2110. 804-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3- MS APCI⁺ m/e 520(M + 1). yl]-quinoline-7-carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide

EXAMPLE 814-[2-(6-Methoxy-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline

Add methanol (19 mg, 0.59 mmol) and sodium hydride (14 mg, 60%dispersion, 0.35 mmol) to a solution of4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (42mg, 0.11.8 mmol) in DMF (0.6 mL) at room temperature. Heat to 110° C.for 3 hours, cool to room temperature, and quench with saturated aqueousammonium chloride (0.5 mL). Concentrate in vacuo, filter, and purify byflash column chromatography (Silica Gel, 20-40% acetone/hexanes) toprovide the title compound 30 mg (73%) as a white solid.

MS APCI⁺ m/e 353 (M+1). TLC (SiO₂): R_(f) 0.20 (1:1 acetone/hexanes)

EXAMPLE 824-[2-(6-Ethoxy-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline

Add sodium hydride (25.5 mg, 0.64 mmol) to a solution of4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (50mg, 0.14 mmol) in ethanol (2.5 mL) at 0° C. Stir the reaction mixture at0° C. for 10 minutes, room temperature for 10 minutes more, and refluxovernight. Cool the reaction mixture to room temperature, quench withsaturated aqueous ammonium chloride (3 mL). Add water (20 mL) andextract the aqueous solution with methylene chloride (3×20 mL). Dry thecombined organic layers with sodium sulfate and purify by flash columnchromatography (SiO₂, 50% ethyl acetate/hexanes) to give the titlecompound 48 mg (94%) as an off-white solid.

MS APCI⁺ m/e 367 (M+1).

EXAMPLE 833-(4-Fluoro-phenyl)-2-(6-methoxy-pyridin-2-yl)-pyrazolo[1,5-a]pyridine

Add sodium hydride (20.7 mg, 60% dispersion in mineral oil, 0.52 mmol)to a solution of2-(6-chloro-pyridin-2-yl)-3-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine(33.5 mg, 0.10 mmol) in DMF (2.5 mL) and methanol (2.5 mL) at roomtemperature. Stir the reaction mixture at room temperature for 4 hoursand at 80° C. for 48 hours. Cool to room temperature and concentrate invacuo. Add water (20 mL) and extract the aqueous solution with methylenechloride (3×20 mL). Dry the combined organic layers with sodium sulfateand concentrate. Purify by flash column chromatography (SiO₂, 50% ethylacetate/hexanes) to give the title compound 31 mg (97%) as an off-whitesolid.

MS APCI⁺ m/e 320 (M+1).

EXAMPLE 842-(6-Ethoxy-pyridin-2-yl)-3-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine

Add sodium hydride (20.7 mg, 0.52 mmol) to a solution of2-(6-chloro-pyridin-2-yl)-3-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine(33.5 mg, 0.10 mmol) in ethanol (2.5 mL) at 0° C. Stir the reactionmixture at 0° C. for 30 minutes and at 80° C. for 48 hours. Cool thereaction mixture to room temperature and concentrate in vacuo Using thesame procedure as above afforded the title compound 31 mg (93%) as anoff-white solid.

MS APCI⁺ m/e 334 (M+1).

EXAMPLE 857-Benzyl-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline

Bubble nitrogen gas through 1 mL of THF for 10 minutes. Add benzylmagnesium chloride (2M in THF, 0.12 mL, 0.24 mmol), zinc chloride (1M indiethyl ether, 0.26 mL, 0.26 mmol). Bubble with nitrogen gas for 15minutes. Add Pd(PPh₃)₂Cl₂ (4 mg, 0.006 mmol),7-bromo-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline(0.05g, 0.12 mmol). Stir at room temperature for 48 hours. Quench withaqueous saturated NH₄Cl solution. Evaporate the solvent in vacuo. Addmethylene chloride. Filter the mixture and concentrate the filtrate invacuo. Chromatograph the residue on silica gel (elute with 50% ethylacetate/hexanes then 100% ethyl acetate). Final purification bypreparative HPLC affords the title compound 20 mg (40%) as a yellowfoam.

MS APCI⁺ m/e 427 (M+1).

EXAMPLE 863-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylicacid methyl ester

Combine7-bromo-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline(0.15 g, 0.36 mmol), tri-o-tolylphosphine (0.38 g, 1.26 mmol),tribuytlamine (0.12 mL, 0.5 mmol), methyl acrylate (0.065 ml, 0.72mmol), anhydrous toluene (3 mL), and DMF (1.5 mL). Bubble nitrogen gasthrough the solution for 20 minutes. Add palladium acetate (4.0 mg,0.018 mmol). Heat the reaction mixture at 80° C. for 48 hours.Chromatograph the residue on silica gel (elute with 2%methanol/methylene chloride, then 4% methanol/methylene chloride).Further purification by preparative HPLC affords the title compound 42mg (28%) as a yellowish solid.

MS APCI⁺ m/e 421 (M+1).

EXAMPLE 873-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylicacid

To a solution of3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylicmethyl ester (0.03 g, 0.07 mmol), THF (1 mL), and H₂O (0.5 mL), add LiOH(0.012 g, 0.29 mmol). Stir the reaction mixture at room temperature for24 hours. Evaporate the solvents in vacuo. Chromatograph the residue onSCX ion-exchange resin (elute with 95% methanol/ethyl acetate, then 100%methanol, then 2M NH₃ in methanol) to afford the title compound 26 mg(93%) as a yellowish solid.

MS APCI⁺ m/e 407 (M+1).

EXAMPLE 884-[2-(6-Ethylsulfanyl-pyridin-2-yl)-pyrazolo[1,5-a]-pyridin-3-yl]-quinoline

Add ethanethiol (0.71 mL, 0.96 mmol) to a solution of4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (37mg, 0.1 mmol) in DMF (2.5 mL) at 0° C. Add sodium hydride (38 mg, 0.96mmol), stir the mixture at room temperature for 72 hours. Dilute thereaction mixture with methylene chloride (50 mL) and wash with water(2×50 mL), brine (1×50 mL). Dry the combined organic layers with sodiumsulfate and concentrate. Purify the residue by flash columnchromatography (SiO₂, 50% ethyl acetate/hexanes) to give the titlecompound 35 mg (91%) as an off-white solid. MS APCI⁺ m/e 383 (M+1).

By the method of EXAMPLE 88 the following compounds were prepared: EX. #Product Name Physical Data 89 4-[2-(6-Phenylsulfanyl-pyridin-2-yl)- MSAPCI⁺ m/e 431 pyrazolo[1,5-a]pyridin-3-yl]-quinoline (M + 1). 904-[2-(6-Morpholin-4-yl-pyridin-2-yl)- MS APCI⁺ m/e 408pyrazolo[1,5-a]pyridin-3-yl]-quinoline (M + 1). 913-(4-Fluoro-phenyl)-2-(6-methylsulfanyl- MS APCI⁺ m/e 336pyridin-2-yl)-pyrazolo[1,5-a]pyridine (M + 1). 923-(4-Methylsulfanyl-phenyl)-2-(6- MS APCI⁺ m/e 364methylsulfanyl-pyridin-2-yl)-pyrazolo[1,5- (M + 1). a]pyridine 93Dimethyl-(2-{4-[2-(6-methyl-pyridin-2-yl)- MS ES⁺ m/e 440pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7- (M + 1). ylsulfanyl}-ethyl)-amine

EXAMPLE 942-(Pyridin-2-yl)-3-(quinolin-4-yl)-pyrazolo[1,5-a]pyridine-5-carboxylicacid dimethylamide

Add trimethylaluminium (0.54 mL, 1.08 mmol.) dropwise to a solution ofdimethylamine (0.45 mL, 0.90 mmol.) in methylene chloride (1 mL) at 0°C. Warm to room temperature and stir for 1 hour. Add2-pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]pyridine-5-carboxylic acidethyl ester (177 mg, 0.45 mmol) in methylene chloride (4 mL), and stirat room temperature for 1 hour and at 80° C. for 24 hours. Cool thereaction mixture to room temperature. Add aqueous solution of potassiumsodium tartarate (20 mL) and stir the solution for 1 hour. Separate theorganic layers and extract the aqueous solution with methylene chloride(2×20 mL). Dry the combined organic layers with sodium sulfate andconcentrate. Purify by flash column chromatography (SiO₂, 20-30%methanol/methylene chloride) to give the title compound 54 mg (31%) as ayellow solid.

MS APCI⁺ m/e 394 (M+1).

EXAMPLE 952-(Pyridin-2-yl)-3-(quinolin-4-yl)-pyrazolo[1,5-a]pyridine-6-carboxylicacid dimethylamide

In the same manner as in the previous example2-pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]pyridine-6-carboxylic acidethyl ester (160 mg, 0.4 mmol) afforded the title compound 21 mg (13%)as a brownish-yellow foam.

MS APCI⁺ m/e 394 (M+1).

EXAMPLE 964-[2-(6-Vinyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline

Add tributylvinylstanane (0.056 mL, 0.182 mmol) to a solution of4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (59mg, 0.165 mmol) in toluene (0.83 mL) at room temperature and bubblenitrogen through the solution for 5 minutes. Addtetrakis(triphenylphosphine) palladium(0) (9 mg, 0.008 mmol) and bubblenitrogen through the solution for 1 minute. Heat the reaction to 110° C.for 15 hours. Purify by flash column chromatography (Silica Gel, 20-40%acetone/hexanes) to provide the title compound 11.5 mg (20%) as a whitesolid.

MS APCI⁺ m/e 349 (M+1).

EXAMPLE 976-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-imidazo[1,2-a]pyridin-2-ylamine

Stir 3-bromo-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine (500 mg,1.74 mmol) in THF (20 ml) at −60° C. and add t-butyl lithium (4 ml, 6.94mmol, 1.7M in pentane). Stir for 1 hour, then add tri-isopropyl borate(1.2 ml, 5.2 mmol) and warm to 0° C. for 1 hour. Quench with 1M HCl (5ml). Concentrate in vacuo and redissolve in a 2:1 toluene/methanolmixture (30 ml). Adjust to pH 8 with aqueous 2M Na₂CO₃. Add 100 mgPd(PPh₃)₄ and2,2,2-trifluoro-N-(6-iodo-imidazo[1,2-a]pyridin-2-yl)-acetamide (200 mg,563 mmol) and heat to 90° C. for 18 hours. Acidify with 1M HCl andextract with ethyl acetate (3×100 ml). Neutralize aqueous layer with 5NNaOH and extract with ethyl acetate (3×100 ml). Concentrate organiclayer in vacuo and purify on Silica gel (eluting with 70/30Hexane/EtOAc). MS ES⁺ m/e 341.1 (M+1).

EXAMPLE 986-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-1H-benzoimidazol-2-ylamine

A solution of2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-boronic acid (0.5 g,crude) and 6-iodo-1-[(1-methylethyl)sulfonyl-1H-benzimidazol-2-amine(0.2 g, 1.04 mmol) in toluene (20 mL) and MeOH (4 mL) is treated withNa₂CO₃ (111.0M aqueous, 10 mL) and (PPh₃)₄Pd (100 mg) and then heated toreflux overnight. The reaction mixture is then cooled, diluted in EtOAc,and the organic phase is washed with water and then brine. The organicsolution is dried over MgSO₄, filtered, and the solvent removed invacuo. The residue is purified by silica gel column chromatography toafford 0.026 g of6-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-1-propane-2-sulfonyl)-1H-benzimidazol-2-ylamineMS ES⁺ m/e 447.1 (M+1). This material (13 mg, 0.029 mmol) isdesulfonylated by heating in 1:1 acetonitrile:0.5 NaOH (10 ml) at 60° C.for 30 minutes. Dilution with water and extraction with methylenechloride (3×20 ml), followed by concentration of the organic layer invacuo. Provides the desired product: MS ES⁺ m/e 341.0 (M+1).

EXAMPLE 99[3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-6-yl]-methanol

Stir EXAMPLE 49 (150 mg, 0.4 mmol) in ether at room temperature Addlithium aluminum hydride (100 mg) slowly and stir for 1 hour. Quenchwith EtOAc (10 ml) and filter. Concentrate filtrate in vacuo and purifyon silica gel (eluted with 90/10 methylene chloride). MS ES⁺ m/e 334.1(M+1).

EXAMPLE 1006-Allyloxymethyl-3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine

A solution of EXAMPLE 99 (0.13 g, 0.39 mmol) and 1-bromo-3-chloropropane(0.06 g, 0.39 mmol) in DMF (10 mL) was treated with cesium carbonate(0.14 g, 0.43 mmol) and heated to 80° C. The reaction is stirredovernight and is diluted with EtOAc and water. The organic phase isseparated and washed with brine. After drying over Na₂SO₄, the organicphase is filtered, and the solvent removed to afford 0.04 g (27%) ofproduct. MS ES⁺ m/e 374.0 (M+1).

EXAMPLE 1014-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide

Dissolve EXAMPLE 75 (0.065 g, 0.16 mmol) in3-pyrrolidin-1-yl-propylamine (8 mL). Heat the solution to 80-100° C.for 48 hours. Concentrate the mixture. Add dichloromethane (25 mL) andwater (20 mL) to the residue. Separate the organic layer and wash withwater (2×20 mL) and brine (20 mL). Dry the organic layer with sodiumsulfate. Filter and concentrate to afford crude product. Chromatograph(SiO₂, 1.5-4% MeOH in CH₂Cl₂) to give the title compound 37 mg (33%) asa pale yellow solid.

TLC: Rf=0.17 (silica gel, 10% CH₂Cl₂/MeOH)

MS ES⁺ m/e 491 (M+1).

By the method of EXAMPLE 101 the following compounds were prepared:EXAMPLE Product # (Chemical Name) Physical Data 1023-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 408 (M + 1).a]pyridin-3-yl]-quinolin-7-yl}-propionamide 1033-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 479 (M + 1).a]pyridin-3-yl]-quinolin-7-yl}-N-(3-pyrrolidin-1-yl-propyl)-propionamide 104N-(2-Dimethylamino-ethyl)-3-{4-[2-(6-methyl- MS ES⁺ m/e 479 (M + 1).pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]- quinolin-7-yl}-propionamide105 2-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5- MS ES⁺ m/e 450 (M + 1).a]pyridine-5-carboxylic acid (3-dimethylamino- propyl)-amide 1064-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylic acid (2- hydroxy-ethyl)-amide 1074-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 395 (M + 1).a]pyridin-3-yl]-quinoline-7-carboxylic acid hydrazide 1084-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 438 (M + 1).a]pyridin-3-yl]-quinoline-7-carboxylic acid (3- hydroxy-propyl)-amide109 4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 394 (M + 1).a]pyridin-3-yl]-quinoline-7-carboxylic acid methylamide 1104-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 466 (M + 1).a]pyridin-3-yl]-quinoline-7-carboxylic acid (3- ethoxy-propyl)-amide 1114-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 507 (M + 1).a]pyridin-3-yl]-quinoline-7-carboxylic acid (3-morpholin-4-yl-propyl)-amide 1124-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 488 (M + 1).a]pyridin-3-yl]-quinoline-7-carboxylic acid (3-imidazol-1-yl-propyl)-amide 1134-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 465 (M + 1).a]pyridin-3-yl]-quinoline-7-carboxylic acid (3-dimethylamino-propyl)-amide 1144-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 514 (M + 1).a]pyridin-3-yl]-quinoline-7-carboxylic acid [2-(2-methoxy-phenyl)-ethyl]-amide 1154-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 493 (M + 1).a]pyridin-3-yl]-quinoline-7-carboxylic acid (2- morpholin-4-yl-ethyl)-amide 116 4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺m/e 380 (M + 1). a]pyridin-3-yl]-quinoline-7-carboxylic acid amide

EXAMPLE 117Dimethyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}-propyl)-amine

To a solution of4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-ol(0.1 g, 0.28 mmol) in DMF (7 mL) add 3-dimethylaminopropyl chloridehydrochloride (0.14 g, 0.86 mmol) and cesium carbonate (0.56 g, 1.71mmol). Stir at room temperature for 48 hour. Evaporate the DMF. Addmethylene chloride. Wash with water and then brine. Dry the organiclayer over anhydrous Na₂SO₄, filter the mixture, and concentrate themixture in vacuo. Chromatograph the residue on silica gel (elute with100% ethyl acetate, then 1% NH₄OH/5% methanol/94% methylene chloride,then 10% methanol in methylene chloride) to give the title compound 63mg (52%) as an off-white solid.

MS APCI⁺ m/e 438 (M+1).

By the method of EXAMPLE 117 the following compounds were prepared:Product EXAMPLE # (Chemical Name) Physical Data 1184-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS APCI⁺ m/e 466 (M + 1).a]pyridin-3-yl]-7-(2-morpholin-4-yl-ethoxy)- quinoline 119Diisopropyl-(2-{4-[2-(6-methyl-pyridin-2-yl)- MS APCI⁺ m/e 480 (M + 1).pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}- ethyl)-amine 1204-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS APCI⁺ m/e 446 (M + 1).a]pyridin-3-yl]-7-(2-pyrrol-1-yl-ethoxy)- quinoline 121Dimethyl-(1-methyl-2-{4-[2-(6-methyl-pyridin-2- MS APCI⁺ m/e 438 (M +1). yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7- yloxy}-ethyl)-amine 122Methyl-(3-{4-[2-(6-methyl-pyridin-2-yl)- MS APCI⁺ m/e 424 (M + 1).pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}- propyl)-amine 1234-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS APCI⁺ m/e 464 (M + 1).a]pyridin-3-yl]-7-(2-piperidin-1-yl-ethoxy)- quinoline 124Diethyl-(2-{4-[2-(6-methyl-pyridin-2-yl)- MS APCI⁺ m/e 452 (M + 1).pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}- ethyl)-amine 125Dimethyl-{3-[4-(2-pyridin-2-yl-pyrazolo[1,5- MS APCI⁺ m/e 424 (M + 1).a]pyridin-3-yl)-quinolin-7-yloxy]-propyl}-amine 1267-(2-Morpholin-4-yl-ethoxy)-4-(2-pyridin-2-yl- MS ES⁺ m/e 452 (M + 1).pyrazolo[1,5-a]pyridin-3-yl)-quinoline 127Diisopropyl-{2-[4-(2-pyridin-2-yl-pyrazolo[1,5- MS ES⁺ m/e 466 (M + 1).a]pyridin-3-yl)-quinolin-7-yloxy]-ethyl}-amine 1284-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS ES⁺ m/e 480 (M + 1).a]pyridin-3-yl]-7-(3-morpholin-4-yl-propoxy)- quinoline 1291-(3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5- MS APCI⁺ m/e 527 (M +1). a]pyridine-3-yl]-quinolin-7-yloxy}-propyl)-1,3-dihydro-benzoimidazol-2-one

EXAMPLE 1303-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-propionicacid methyl ester

Add Pd/C (10%, 0.46 g) to a solution of3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylicacid methyl ester (0.462 g, 1.1 mmol) in MeOH (10 mL) anddichloromethane (10 mL). Bubble nitrogen for 15 minutes. Connect thehydrogen balloon to the reaction flask and stir overnight. Filterthrough celite and wash the celite pad with dichloromethane (50 mL).Remove the solvent. Chromatograph the residue (elute with 2% MeOH indichloromethane) to give the desired product as a pale yellow solid 0.27g (59%).

¹H NMR (CDCl₃) δ 9.22-9.14 (m, 1H), 8.69-8.61 (m, 1H), 8.37-8.30 (m,1H), 7.84-7.74 (m, 2H), 7.73-7.65 (m, 1H), 7.63-7.54 (m, 1H), 7.47-7.37(m, 1H), 7.35-7.29 (m, 2H), 7.08-6.98 (m, 2H), 3.68 (s, 3H), 3.25-3.16(m, 2H), 2.82-2.71 (m, 2H), 2.03 (s, 3H). TLC: R_(f)=0.4 (silica gel,10% CH₂Cl₂/MeOH)

MS ES⁺ m/e 423 (M+1).

EXAMPLE 131Diethyl-{3-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-propyl}-amine

A solution of7-(3-chloro-propoxy)-4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline(0.1 g, 0.24 mmol) in DMF was treated with N,N-diethylamine (excess) andKI (catalytic). The reaction was heated to 60° C. in a sealed tube andstirred overnight. The reaction was quenched with water and extractedwith CH₂Cl₂. The organic was dried and the solvent removed. The crudewas purified by silica gel column to afford the desired product. MS ES⁺m/e 452 (M+1).

By the method of EXAMPLE 131 the following compounds were prepared:Product (Chemical Starting Starting EX # Name) Material A Material BPhysical Data Comments 132 Ethyl- 7-(3-Chloro- N-Ethyl-N- MS ES⁺ m/emethyl-{3- propoxy)-4-(2- methylamine 438.1 (M + 1). [4-(2-pyridin-2-yl- pyridin-2- pyrazolo[1,5- yl- a]pyridin-3-yl)-pyrazolo[1,5- quinoline a]pyridin- 3-yl)- quinolin-7- yloxy]- propyl}-amine 133 4-(2- 7-(3-Chloro- Pyrrolidine MS ES⁺ m/e Pyridin-2-propoxy)-4-(2- 450.1 (M + 1). yl- pyridin-2-yl- pyrazolo[1,5-pyrazolo[1,5- a]pyridin- a]pyridin-3-yl)- 3-yl)-7-(3- quinolinepyrrolidin- 1-yl- propoxy)- quinoline 134 7-(3- 7-(3-Chloro- PiperidineMS ES⁺ m/e Piperidin-1- propoxy)-4-(2- 464.1 (M + 1). yl- pyridin-2-yl-propoxy)-4- pyrazolo[1,5- (2-pyridin- a]pyridin-3-yl)- 2-yl- quinolinepyrazolo[1,5- a]pyridin- 3-yl)- quinoline 135 Diethyl-{2- 7-(2-Chloro-N,N- MS ES⁺ m/e [4-(2- ethoxy)-4-(2- Diethylamine 438.0 (M + 1).pyridin-2- pyridin-2-yl- yl- pyrazolo[1,5- pyrazolo[1,5-a]pyridin-3-yl)- a]pyridin- quinoline 3-yl)- quinolin-7- yloxy]- ethyl}-amine 136 Dimethyl- 7-(2-Chloro- N,N- MS ES⁺ m/e {2-[4-(2- ethoxy)-4-(2-Dimethylamine 410.2 (M + 1). pyridin-2- pyridin-2-yl- yl- pyrazolo[1,5-pyrazolo[1,5- a]pyridin-3-yl)- a]pyridin- quinoline 3-yl)- quinolin-7-yloxy]- ethyl}- amine

TGF-βReceptor I and II Purification and In Vitro Kinase Reactions

For TGF-βType I (RIT204D) and Type II (RII WT) Receptor Kinases:

The 6×-HIS tagged cytoplasmic kinase domain of each receptor wasexpressed and purified from Sf9 insect cell lysates as briefly describedbelow:

Cell pellets after 48-72 hrs of infection were lysed in lysis buffer(LB: 50 mM Tris pH 7.5, 150 mM NaCl, 50 mM NaF, 0.5% NP40 with freshlyadded 20 mM β-mercaptoethanol, 10 mM imidazole, 1 mM PMSF, 1× EDTA-freeComplete Protease Inhibitor (Boehringer Mannheim).

Cell lysates were clarified by centrifugation and 0.45 uM filtered priorto purification by Ni/NTA affinity chromatography (Qiagen).

Chromatography Protocol:

Equilibrate with 10 CV of LB, load sample, wash with 10 CV RIPA buffer(50 mM Tris pH 7.5, 150 mM NaCl, 1% NP40, 1 mM EDTA, 0.25% sodiumdeoxycholate, added fresh 20 mM β-mercaptoethanol, 1 mM PMSF), wash with10 CV LB, wash with 10 CV 1×KB (50 mM Tris pH 7.5, 150 mM NaCl, 4 mMMgCl₂, 1 mM NaF, 2 mM mercaptoethanol), elute with a linear gradient of1× KB containing 200 mM Imidazole.

Both enzymes were approximately 90% pure and had autophosphorylationactivity.

Reactions: 170-200 nM enzyme in 1×KB, compound dilution series in1×KB/16% DMSO (20 uM to 1 mM final concentration with 4% DMSO finalconcentration), reactions started by adding ATP mix (4 uM ATP/1 uCi³³P-γ-ATP final concentrations) in 1× KB.

Reactions were incubated at 30° C. for 1 hr RIT204D or 40 min for RIIWT. Reactions were stopped and quantitated using standard TCA/BSAprecipitation onto Millipore FB glass fiber filter plates and by liquidscintillation counting on a MicroBeta JET.

TGF-β Receptor I

All exemplified compounds were tested essentially as described above andwere found to inhibit the TGF-beta Type I Receptor Kinase with an IC50of at least 10 uM. As representative of the series, Examples 43, 47, 53,and 56, inhibited the TGF-beta Type I kinase with IC50's, of 0.152 uM,0.175 uM, 0.806 uM, and 0.102 uM, respectively.

TGF-βReceptor II

As above, all exemplified compounds were found to inhibit the TGF-betaType II Receptor Kinase with an IC50 of at least 20 uM. Asrepresentative of the series, Examples 43, 47, 53 and 56 inhibited theTGF-beta Type II kinase with IC50's of 3.17 uM, 5.10 uM, 20 uM, and0.377 uM, respectively.

p38α In Vitro Kinase Assay

Active p38α/SAPK2α was purchased from Upstate Biotechnology(cat#14-251). A known p38× substrate from EGFR was used in the assay(Young, et al. (1997) JBC 272:12116-12121).

Reactions were performed in 1× kinase buffer (25 mM Tris-HCl pH 7.5, 5mM β-glycerophosphate, 2 mM DTT, 0.1 mM Na₃VO₄, 10 mM MgCl₂, 1 uMMicrocystin) with 5 nM p38α, 62.5 uM substrate, 40 uM to 0.2 nM compounddilution series in 1× KB/16% DMSO (final 4% DMSO concentration).Reactions were started by addition of 100 uM ATP (final concentration)with 1 uCi ³³P-γ-ATP in 1× KB and incubated at 30° C. for 40 min.Reactions were stopped with H₃PO₄ and quantitated on Millipore PHphosphocellulose filter plates by liquid scintillation counting on aMicroBeta JET.

Representative data for compounds of the current invention with the p38αIC50 <20.00 (uM): Examples 45, 46, 78 and 117 gave, respectively, IC₅₀'sof 0.390, 0.369, 0.233 and 0.078 uM.

MV1LU p3TP-LUX Assay

A stable Mv1Lu clone (C1) containing the p3TP-Lux reporter was createdby standard transfection and puromycin selection protocols. This stableclone was used to screen the example compounds for their ability toinhibit TGF-β dependent luciferase production as briefly describedbelow:

-   -   1. Plated Mv1Lu C1 cells in Wallac™ Black Isoplates.    -   2. Allowed cells to adhere overnight.    -   3. Removed media and replaced with 0.5% FBS DMEM media.    -   4. Added the compound dilution series in 0.5% FBS/DMEM        containing 1% DMSO such that the final compound concentration        ranged from 20 uM to 0.1 nM and the final DMSO concentration was        0.2%.    -   5. Incubated at 37° C./5% CO₂ for 2 hrs.    -   6. Added 0.5% FBS/DMEM as control or TGF-β1 diluted. in 0.5%        FBS/DMEM (final concentration of 10 pM) to the −/+TGF-β wells        respectively.    -   7. Incubated for 16-20 hrs. at 37° C./5% CO₂.    -   8. Removed media and rinsed 1× with PBS.    -   9. Removed PBS and lysed the cells with 1× Passive. Lysis Buffer        (Promega) at room temperature.    -   10. Counted relative luciferase activity on the MicroBeta JET by        injecting Luciferase Assay Reagent II (PROMEGA).

The use of the above assay in measuring TGF-β responsive activity isdescribed in Wrana, et al. Cell 71: 1003-1014 (1992).

As above, all exemplified compounds were found to inhibit TGF-betadependent luciferase production with an IC50 of at least 20 uM. Asrepresentative of the series, Examples 43, 47, 53 and 56 inhibitedluciferase production with IC50's of 0.120 uM, 0.100 uM, 0.487 uM, and0.135 uM, respectively.

Pharmaceutical Compositions

The compositions of the present invention are therapeutically effectiveTGF-β inhibitors, noted above. The composition may be formulated withcommon excipients, diluents or carriers, and compressed into tablets, orformulated elixirs or solutions for convenient oral administration oradministered by intramuscular intravenous routes. The compounds can beadministered transdermally and maybe formulated as sustained reliefdosage forms and the like.

The method of treating a human patient according to the presentinvention includes administration of the TGF-β kinase inhibitors. TheTGF-β kinase inhibitors are formulated into formulations which may beadministered by the oral and rectal routes, topically, parenterally,e.g., by injection and by continuous or discontinuous intra-arterialinfusion, in the form of, for example, tablets, lozenges, sublingualtablets, sachets, cachets, elixirs, gels, suspensions, aerosols,ointments, for example, containing from 1 to 10% by weight of the activecompound in a suitable base, soft and hard gelatin capsules,suppositories, injectable solutions and suspensions in physiologicallyacceptable media, and sterile packaged powders adsorbed onto a supportmaterial for making injectable solutions. Advantageously for thispurpose, compositions may be provided in dosage unit form, preferablyeach dosage unit containing from about 5 to about 500 mg (from about 5to 50 mg in the case of parenteral or inhalation administration, andfrom about 25 to 500 mg in the case of oral or rectal administration)the compounds. Dosages from about 0.5 to about 300 mg/kg per day,preferably 0.5 to 20 mg/kg, of active ingredient may be administeredalthough it will, of course, readily be understood that the amount ofthe compound actually to be administered will be determined by aphysician, in the light of all the relevant circumstances including thecondition to be treated, the choice of compound to be administered andthe choice of route of administration and therefore the above preferreddosage range is not intended to limit the scope of the present inventionin any way.

The formulations useful for separate administration of the TGF-βinhibitors will normally consist of at least one compound selected fromthe compounds specified herein mixed with a carrier, or diluted by acarrier, or enclosed or encapsulated by an ingestible carrier in theform of a capsule, sachet, cachet, paper or other container or by adisposable container such as an ampoule. A carrier or diluent may be asolid, semi-solid or liquid material which serves as a vehicle,excipient or medium for the active therapeutic substance. Some examplesof the diluents or carrier which may be employed in the pharmaceuticalcompositions of the present invention are lactose, dextrose, sucrose,sorbitol, mannitol, propylene glycol, liquid paraffin, white softparaffin, kaolin, fumed silicon dioxide, microcrystalline cellulose,calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol,starch, modified starches, gum acacia, calcium phosphate, cocoa butter,ethoxylated esters, oil of theobroma, arachis oil, alginates,tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitanmonolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitantrioleate, sorbitan sesquioleate and oleyl alcohol and propellants suchas trichloromonofluoromethane, dichlorodifluoromethane anddichlorotetrafluoroethane. In the case of tablets, a lubricant may beincorporated to prevent sticking and binding of the powdered ingredientsin the dies and on the punch of the tableting machine. For such purposethere may be employed for instance aluminum, magnesium or calciumstearates, talc or mineral oil.

Preferred pharmaceutical forms of the present invention are capsules,tablets, suppositories, injectable solutions, creams and ointments.Especially preferred are formulations for inhalation application, suchas an aerosol, for injection, and for oral ingestion.

1. A compound of Formula I:

Wherein: R₁ is unsubstituted or substituted pyridine; unsubstituted orsubstituted furyl; or unsubstituted or substituted thiophenyl; whereinthe substitution may be one or more of the following: (C1-C6)alkyl,(C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylthio, trifluoromethyl, halo,N-morpholino, or phenylthio; R₂ is unsubstituted or substitutedquinoline; unsubstituted or substituted phenyl; unsubstituted orsubstituted naphthalene; unsubstituted or substituted pyridine;unsubstituted or substituted quinazoline; unsubstituted or substitutedcinnoline; unsubstituted or substituted indole; unsubstituted orsubstituted imidazo[1,2-a]pyridin-2-yl; unsubstituted or substitutedbenzofuran; unsubstituted or substituted dihydrobenzofuran;unsubstituted or substituted dihydrobenzo[1,4]dioxane; unsubstituted orsubstituted benzodioxolane; unsubstituted or substituted benzothiophene;unsubstituted or substituted 2-aminobenzimidazole; unsubstituted orsubstituted imidazo[1,2-a]pyridine; wherein the substitution mayindependently be one or more of the following: hydrogen, (C1-C6)alkyl,(C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalide, (C1-C6)alkoxy,(C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C1-C6)alkylthio,(C1-C6)alkylsulphinyl, (C1-C6)alkylsulphonyl, (C₁-C6)alkylamino,di-[(C1-C6)alkyl]amino, (C1-C6)alkoxycarbonyl, N-(C1-C6)alkylcarbamoyl,N,N-di-[(C1-C6)alkyl]carbamoyl, aminooxy, N-(C1-C6)alkyl aminooxy,N,N-di-[(C1-C6)alkyl]aminooxy, (C2-C6)alkanoyl, (C2-C6)alkanoyloxy,(C2-C6)alkanoylamino, N-(C1-C6)alkyl-(C2-C6)alkanoylamino,(C3-C6)alkenoylamino, N-(C1-C6)alkyl-(C3-C6)alkenoylamino,(C3-C6)alkynoylamino, N-(C1-C6)alkyl-(C3C6)alkynoylamino, sulphamoyl,N-(C1-C6)alkylsulphamoyl, N,N-di-[(C1-C6)alkyl]sulphamoyl,(C1-C6)alkanesulphonylamino, N-(C1-C6)alkyl-(C1-C6)alkanesulphonylamino,carboxamide, phenyl, thiophenyl, aminophenyl, phenylthio, halo, cyano,pyridinyl, arylalkyl, hydroxy, N-pyrrolidino, N-morpholino, carboxyl,[5-phenyl-1,2,4-oxadiazole-3-yl]methoxy, 6-methyl-pyridazin-3-yl-oxy,(5-oxo-2-pyrrolidinyl)methoxy, 2-(4,5-dihydro-1H-imidazolyl),N,N-dialkylcarbamoyloxy, 1-hydroxy-1-methylethyl, 4-fluorophenyl,3,4-methylenedioxyphenyl, trifluoromethyl, trifluoromethoxy, or a groupof the formula

wherein: X₁ is O, N, S, SO₂, NR₁₃, C(O), or bond; Q₁ is hydrogen,phenyl, 5-(2,2-difluoro-1,3-benzodioxolyl), C(O)Q₅, or pyridyl when mand n are independently 0-2, except when one is 0 the other cannot be 0;Q₁ is OR₁₁, NR₁₁R₁₂, halo, N-morpholino, N-piperazino-N′R₁₃,N-imidazolyl, N-pyrazolyl, N-triazolyl, N-(4-piperidinylpiperidine),SO₂R₁₄, SOR₁₄, NHSO₂R₁₅, acetamido, N-phthalimido, N-oxazolidino,N-imidazolino, N-benzoxazolidino, N-pyrolidinonyl,N(N′-methylbenzimidazolino), N,N-di(C1-C4)alkylamino(C1-C4)alkoxy,N-benzimidazolino; Q₅ is hydroxy, methoxy, amino, diethylamino,dimethylamino; R₁₀ is hydrogen, halo, (C1-C6)alkyl; R₁₁ and R₁₂ areindependently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, arylalkyl,(C3-C8)cycloalkyl, (C3-C8)cycloalkylmethyl, 4-(N-methylpiperidinyl),pyridyl, or R₁₁ and R₁₀ can be taken together to form a 4, 5, 6, or 7membered ring, or R₁₁ and R₁₂ can be taken together to form a 3, 4, 5,6, or 7 membered ring; R₁₃ is hydrogen, (C1-C6)alkyl, 2-methoxyphenyl,2-pyridimidinyl; R₁₄ is 2-pyrimidinyl, N-methyl-2-imidazolyl,4-chlorophenyl, 2-pyridylmethyl; R₁₅ is (C1-C6)alkyl,N-methyl-4-imidazolyl; R₁₆ is hydrogen, halo, arylalkyl, or aryl or agroup of the formula:

wherein: Q₂ is hydrogen, 4-imidazolyl, or C(O)NR₂₄R₂₅ when o and p areindependently 0-2; Q₂ is OR₂₃, NR₂₄R₂₅, or N-morpholino, when o and pare independently 0-2, but one or the other of o or p is not 0; R₂₀ ishydrogen, or (C1-C6)alkyl; R₂₁ is hydrogen, (C1-C6)alkyl, or R₂₁ and R₂₀can be taken together to form a 4, 5, 6, or 7 membered ring; R₂₂ ishydrogen, (C1-C6)alkyl, arylalkyl, aryl, or R₂₁ and R₂₂ can be takentogether to be a 3, 4, 5, 6, 7 membered ring; R₂₃ is hydrogen or(C1-C6)alkyl; R₂₄ is hydrogen, (C1-C6)alkyl, or R₂₄ and R₂₅ can be takentogether to form a 3, 4, 5, 6, or 7 membered ring, or R₂₄ and R₂₀ can betaken together to form a 6 or 7 membered ring; R₂₅ is hydrogen,(C1-C6)alkyl, or acetyl, or a group of the formula

wherein: R₃₀ is hydrogen, or (C1-C6)alkyl; R₃] is hydrogen,(C1-C6)alkyl, 2-pyridyl, pyridylmethyl, amino, or hydroxy, or a group ofthe formula

wherein: R₃₂ and R₃₃ are each independently hydrogen, (C1-C6)alkyl,acetyl, (C1-C4)alkylsulphonyl, or R₃₂ and R₃₃ can be taken together toform a 4, 5, 6, or 7 membered ring, or a group of the formula

wherein: X₂ is CH₂, O, or N; q is 0-3; Q₃ is NR₃₆R₃₇, or OR₃₈, and R₃₅is hydrogen, or R₃₅ and Q₃ can be taken together to form a 5 memberedring; R₃₆, R₃₇, and R₃₈ are each independently hydrogen, or(C1-C6)alkyl, or a group of the formula

wherein: X₃ is cyano, carboxamide, N,N-dimethylcarboxamide,N,N-dimethylthiocarboxamide, N,N-dimethylaminomethyl,4-methylpiperazin-1yl-methyl or carboxylate, or a group of the formula

wherein: Q₆ is NR₄₁R₄₂; r is 2-3; R₄₀ is hydrogen, or (C1-C6)alkyl; R₄₁and R₄₂ are hydrogen, (C1-C6)alkyl, or R₄₁ and R₄₀ can be taken togetherto form a 6 or 7 membered ring, or a group of the formula

wherein: Q₇ is hydroxy, methoxy, dimethylamino, or N-piperidinyl; andwherein R₇ is hydrogen; benzyl; aryl; C₁-C₄ alkyl; halogen;—CO₂(C₁-C₄)alkyl; —CONR₆R₆; C₁-C₄ alcohol; —SO₂(C1-C4)alkyl; —COR₈;wherein R₆ is (C1-C4)alkyl R₉; R₈ is (C1-C4)alkyl or (C2-C4)alkenyl; andR₉ is NR₃R₄, wherein R₃ and R₄ are each independently (C1-C4)alkyl; andthe pharmaceutically acceptable salts, esters and prodrugs thereof.
 2. Acompound according to claim 1 of the formula:

where R₂ is substituted or unsubstituted 4-quinoline.
 3. A compoundaccording to claim 1 of the formula:

where R₂ is substituted or unsubstituted phenyl.
 4. A compound of ofclaim 1 where R₁ is substituted or unsubstituted 2-pyridyl.
 5. Acompound of of claim 1 where R₇ is hydrogen.
 6. A compound according toclaim 1 selected from the group comprising:4-[2-(6-Ethyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid methyl ester,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-6-carboxylicacid methyl ester,4-(5-Benzyl-2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline-7-carboxylicacid methyl ester,3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-6-carboxylicacid (2-dimethylamino-ethyl)-amide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-6-carboxylicacid (2-dimethylamino-ethyl)-amide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid (2-dimethylamino-ethyl)-amide,5-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-benzofuran-2-carboxylicacid (2-dimethyl amino-ethyl)-amide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid[3-(4-methyl-piperazin-1-yl)-propyl]-amide,4-[2-(6-Methoxy-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,4-[2-(6-Ethoxy-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,3-(4-Fluoro-phenyl)-2-(6-methoxy-pyridin-2-yl)-pyrazolo[1,5-a]pyridine,2-(6-Ethoxy-pyridin-2-yl)-3-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine,7-Benzyl-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylicacid methyl ester,3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylicacid,4-[2-(6-Ethylsulfanyl-pyridin-2-yl)-pyrazolo[1,5-a]-pyridin-3-yl]-quinoline,4-[2-(6-Phenylsulfanyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,4-[2-(6-Morpholin-4-yl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,3-(4-Fluoro-phenyl)-2-(6-methylsulfanyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine,3-(4-Methylsulfanyl-phenyl)-2-(6-methylsulfanyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine,Dimethyl-(2-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-ylsulfanyl}-ethyl)-amine,2-(Pyridin-2-yl)-3-(quinolin-4-yl)-pyrazolo[1,5-a]pyridine-5-carboxylicacid dimethylamide,2-(Pyridin-2-yl)-3-(quinolin-4-yl)-pyrazolo[1,5-a]pyridine-6-carboxylicacid dimethylamide,4-[2-(6-Vinyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline,6-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-imidazo[1,2-a]pyridin-2-yl-amine,6-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-1H-benzoimidazol-2-yl-amine,[3-(4-Fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-6-yl]-methanol,6-Allyloxymethyl-3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide,3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-propionamide,3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-N-(3-pyrrolidin-1-yl-propyl)-propionamide,N-(2-Dimethylamino-ethyl)-3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-propionamide,2-Pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]pyridine-5-carboxylic acid(3-dimethylamino-propyl)-amide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid (2-hydroxy-ethyl)-amide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid hydrazide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid (3-hydroxy-propyl)-amide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid methylamide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid (3-ethoxy-propyl)-amide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid (3-morpholin-4-yl-propyl)-amide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid (3-imidazol-1-yl-propyl)-amide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid (3-dimethylamino-propyl)-amide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid[2-(2-methoxy-phenyl)-ethyl]-amide,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline-7-carboxylicacid amide,Dimethyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}-propyl)-amine,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-7-(2-morpholin-4-yl-ethoxy)-quinoline,Diisopropyl-(2-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}-ethyl)-amine,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-7-(2-pyrrol-1-yl-ethoxy)-quinoline,Dimethyl-(1-methyl-2-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}ethyl)-amine,Methyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl-oxy}-propyl)-amine,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-7-(2-piperidin-1-yl-ethoxy)-quinoline,Diethyl-(2-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yloxy}-ethyl)-amine,Dimethyl-{3-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-propyl}-amine,7-(2-Morpholin-4-yl-ethoxy)-4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline,Diisopropyl-{2-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-ethyl}-amine,4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-7-(3-morpholin-4-yl-propoxy)-quinoline,1-(3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-yl]-quinolin-7-yloxy}-propyl)-1,3-dihydro-benzoimidazol-2-one3-{4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-propionicacid methyl ester,Diethyl-{3-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-propyl}-amine,Ethyl-methyl-{3-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-propyl}-amine,4-(2-Pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-7-(3-pyrrolidin-1-yl-propoxy)-quinoline,7-(3-Piperidin-1-yl-propoxy)-4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline,Diethyl-{2-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-ethyl}-amine,Dimethyl-{2-[4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-yloxy]-ethyl}-amine,and the pharmaceutically acceptable salts, esters and prodrugs thereof.7. A pharmaceutical formulation comprising a compound according to claim1 in admixture with an acceptable pharmaceutical carrier or excipient.8. A method of inhibiting TGF-beta Type I Receptor Kinase in a mammalcomprising administering to a mammal in need of such treatment anTGF-beta Type I receptor kinase inhibiting amount of a compoundaccording to compound according to claim
 1. 9. A method of treatingconditions resulting from excessive production of TGF-beta in a mammalin need of such treatment comprising administering aTGF-beta-suppressing amount of a compound according to claim
 1. 10. Amethod of treating cancer in a mammal in need thereof comprisingadministering to said patient a therapeutically effective amount acompound according to claim
 1. 11. (canceled)
 12. (canceled) 13.(canceled)